Biochemistry, Genetics and Molecular Biology › Molecular Biology

Retinoids in leukemia and cellular processes

Works Count: 55596

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Description

This cluster of papers explores the role of retinoic acid in various biological processes, including its involvement in acute promyelocytic leukemia, gene expression regulation, vitamin A metabolism, and embryonic development. It also discusses the interaction of retinoic acid with nuclear receptors such as RXR, the use of arsenic trioxide in treatment, and the potential for differentiation therapy.

Keywords

Retinoic Acid; Acute Promyelocytic Leukemia; RXR; PML Nuclear Bodies; Arsenic Trioxide; Gene Expression Regulation; Vitamin A Metabolism; Nuclear Receptors; Differentiation Therapy; Embryonic Development

Fusion proteins of the retinoic acid receptor-α recruit histone deacetylase in promyelocytic leukaemia

1998-02-01

F Grignani , Silvia De Matteis , Clara Nervi +7 more

Embryonic retinoic acid synthesis is essential for early mouse post-implantation development

1999-04-01

Karen Niederreither , Vemparala Subbarayan , Pascal Dollé +1 more

Role of the histone deacetylase complex in acute promyelocytic leukaemia

1998-02-19

Richard J. Lin , László Nagy , Satoshi Inoue +3 more

Deconstructing a Disease: RAR, Its Fusion Partners, and Their Roles in the Pathogenesis of Acute Promyelocytic Leukemia

1999-05-15

Ari Melnick , Jonathan D. Licht

Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia

1988-08-01

Meng‐Er Huang , YC Ye , S R Chen +5 more

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The HL-60 promyelocytic leukemia cell line: proliferation, differentiation, and cellular oncogene expression

1987-11-01

SJ Collins

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A decade of molecular biology of retinoic acid receptors

1996-07-01

Pierre Chambon

Retinoids play an important role in development, differentiation, and homeostasis. The discovery of retinoid receptors belonging to the superfamily of nuclear ligand-activated transcriptional regulators has revolutionized our molecular understanding as … Retinoids play an important role in development, differentiation, and homeostasis. The discovery of retinoid receptors belonging to the superfamily of nuclear ligand-activated transcriptional regulators has revolutionized our molecular understanding as to how these structurally simple molecules exert their pleiotropic effects. Diversity in the control of gene expression by retinoid signals is generated through complexity at different levels of the signaling pathway. A major source of diversity originates from the existence of two families of retinoid acid (RA) receptors (R), the RAR isotypes (alpha, beta, and gamma) and the three RXR isotypes (alpha, beta, and gamma), and their numerous isoforms, which bind as RXR/RAR heterodimers to the polymorphic cis-acting response elements of RA target genes. The possibility of cross-modulation (cross-talk) with cell-surface receptors signaling pathways, as well as the finding that RARs and RXRs interact with multiple putative coactivators and/or corepressors, generates additional levels of complexity for the array of combinatorial effects that underlie the pleiotropic effects of retinoids. This review focuses on recent developments, particularly in the area of structure-function relationships.

Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RARα with a novel putative transcription factor, PML

1991-08-01

Akira Kakizuka , Wilson H. Miller , Kazuhiko Umesono +5 more

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Retinol-Binding Protein 4 and Insulin Resistance in Lean, Obese, and Diabetic Subjects

2006-06-14

Timothy E. Graham , Qin Yang , Matthias Blüher +7 more

Insulin resistance has a causal role in type 2 diabetes. Serum levels of retinol-binding protein 4 (RBP4), a protein secreted by adipocytes, are increased in insulin-resistant states. Experiments in mice … Insulin resistance has a causal role in type 2 diabetes. Serum levels of retinol-binding protein 4 (RBP4), a protein secreted by adipocytes, are increased in insulin-resistant states. Experiments in mice suggest that elevated RBP4 levels cause insulin resistance. We sought to determine whether serum RBP4 levels correlate with insulin resistance and change after an intervention that improves insulin sensitivity. We also determined whether elevated serum RBP4 levels are associated with reduced expression of glucose transporter 4 (GLUT4) in adipocytes, an early pathological feature of insulin resistance.We measured serum RBP4, insulin resistance, and components of the metabolic syndrome in three groups of subjects. Measurements were repeated after exercise training in one group. GLUT4 protein was measured in isolated adipocytes.Serum RBP4 levels correlated with the magnitude of insulin resistance in subjects with obesity, impaired glucose tolerance, or type 2 diabetes and in nonobese, nondiabetic subjects with a strong family history of type 2 diabetes. Elevated serum RBP4 was associated with components of the metabolic syndrome, including increased body-mass index, waist-to-hip ratio, serum triglyceride levels, and systolic blood pressure and decreased high-density lipoprotein cholesterol levels. Exercise training was associated with a reduction in serum RBP4 levels only in subjects in whom insulin resistance improved. Adipocyte GLUT4 protein and serum RBP4 levels were inversely correlated.RBP4 is an adipocyte-secreted molecule that is elevated in the serum before the development of frank diabetes and appears to identify insulin resistance and associated cardiovascular risk factors in subjects with varied clinical presentations. These findings provide a rationale for antidiabetic therapies aimed at lowering serum RBP4 levels.

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The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor α gene to a novel transcribed locus

1990-10-01

Hugues de Thé , Christine Chomienne , Michel Lanotte +2 more

9-Cis retinoic acid stereoisomer binds and activates the nuclear receptor RXRα

1992-01-01

Arthur A. Levin , Laurie J. Sturzenbecker , Sonja Kazmer +7 more

Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling

1992-01-01

Steven A. Kliewer , Kazuhiko Umesono , David J. Mangelsdorf +1 more

The RXR heterodimers and orphan receptors

1995-12-01

David J. Mangelsdorf , Ronald M. Evans

Human promyelocytic leukemia cells in culture differentiate into macrophage-like cells when treated with a phorbol diester.

1979-06-01

G Rovera , D Santoli , C H Damsky

When suspension cultures of human promyelocytic leukemia cells (line HL60) were treated with 12-O-tetradecanoylphorbol 13-acetate (TPA; 1.6-160 nM), more than 80% of the cells adhered to the plastic substrate within … When suspension cultures of human promyelocytic leukemia cells (line HL60) were treated with 12-O-tetradecanoylphorbol 13-acetate (TPA; 1.6-160 nM), more than 80% of the cells adhered to the plastic substrate within 24 hr. Within the same time period the immature azurophilic granulations typical of HL60 promyelocytic cells disappeared and the nuclear chromatin became more condensed, but the nucleolus was retained. The attached cells stopped dividing and synthesizing DNA. The phenomenon was irreversible and independent of the continuous presence of TPA. Approximately 60% of the untreated cells and of TPA-treated cells bore surface Fc receptors for IgG. Under the experimental conditions used, about 10% of the TPA-treated cells were also able to phagocytize IgG-coated erythrocytes and more than 80% were able to phagocytize latex beads, but untreated controls were unable to do so. Cellular levels of NADase, acid phosphatase, and non-specific esterase were markedly increased after treatment with TPA, whereas little or no increase was seen after treatment with dimethyl sulfoxide (Me2SO), a drug that induces myeloid differentiation of HL60 cells. Peroxidase activity was lower in TPA-treated and Me2SO-treated cells than in HL60 cells. More lysozyme was found in the medium of TPA-treated cells than in the medium of untreated or Me2SO-treated cells. These data indicate that, after treatment with TPA, human promyelocytic leukemia cells can differentiate into cells that have several characteristics of macrophages.

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Direct repeats as selective response elements for the thyroid hormone, retinoic acid, and vitamin D3 receptors

1991-06-01

Kazuhiko Umesono , Kevin K. Murakami , Catherine C. Thompson +1 more

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Chemistry and metabolism of lipids in the vertebrate retina

1983-01-01

Steven J. Fliesler , Robert E. Anderson

Effects of vitamin A and its analogs (retinoids) on normal and neoplastic cells

1980-03-01

Reuben Lotan

Vitamin effects on the immune system: vitamins A and D take centre stage

2008-08-11

J. Rodrigo Mora , Makoto Iwata , Ulrich H. von Andrian

Acute promyelocytic leukemia: from highly fatal to highly curable

2008-02-25

Zhenyi Wang , Zhu Chen

Autocrine growth factors and cancer

1985-02-01

Michael B. Sporn , Anita B. Roberts

Nuclear Receptor Repression Mediated by a Complex Containing SMRT, mSin3A, and Histone Deacetylase

1997-05-01

László Nagy , Hung‐Ying Kao , Debabrata Chakravarti +5 more

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Retinoic Acid Synthesis and Signaling during Early Organogenesis

2008-09-01

Gregg Duester

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9-cis retinoic acid is a high affinity ligand for the retinoid X receptor

1992-01-01

Richard A. Heyman , David J. Mangelsdorf , Jacqueline A. Dyck +4 more

Crystal structure of the ligand-binding domain of the human nuclear receptor RXR-α

1995-06-01

William Bourguet , Marc Ruff , Pierre Chambon +2 more

A human retinoic acid receptor which belongs to the family of nuclear receptors

1987-12-01

Martin Petkovich , Nigel J. Brand , Andrée Krust +1 more

Identification of a retinoic acid responsive element in the retinoic acid receptor & beta;gene

1990-01-11

Hugues de Thé , María dM Vivanco , Pierre Tiollais +2 more

The PML-RARα fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR

1991-08-01

Hugues de Thé , Catherine Lavau , Agnès Marchio +3 more

Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor

1995-10-01

Andreas Hörlein , Anders M. Näär , Thorsten Heinzel +7 more

The induction of differentiation in teratocarcinoma stem cells by retinoic acid

1978-10-01

Sidney Strickland , Vijak Mahdavi

Identification of a receptor for the morphogen retinoic acid

1987-12-01

Vincent Giguère , Estelita S. Ong , Prudimar Segui +1 more

Nuclear Receptors, RXR, and the Big Bang

2014-03-01

Ronald M. Evans , David J. Mangelsdorf

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Nuclear receptor that identifies a novel retinoic acid response pathway

1990-05-01

David J. Mangelsdorf , Estelita S. Ong , Jacqueline A. Dyck +1 more

Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes

2005-07-01

Qin Yang , Timothy E. Graham , Nimesh Mody +6 more

Purification, cloning, and RXR identity of the HeLa cell factor with which RAR or TR heterodimerizes to bind target sequences efficiently

1992-01-01

Mark Leid , Philippe Kastner , Ruth J. Lyons +7 more

LXR, a nuclear receptor that defines a distinct retinoid response pathway.

1995-05-01

P J Willy , Kazuhiko Umesono , Estelita S. Ong +3 more

We have identified a new retinoid response pathway through which 9-cis retinoic acid (9cRA) activates transcription in the presence of LXR alpha, a member of the nuclear receptor superfamily. LXR … We have identified a new retinoid response pathway through which 9-cis retinoic acid (9cRA) activates transcription in the presence of LXR alpha, a member of the nuclear receptor superfamily. LXR alpha shows a specific pattern of expression in visceral organs, thereby restricting the response to certain tissues. Retinoid trans-activation occurs selectively on a distinct response element termed an LXRE. Significantly, neither RXR homodimers nor RXR/RAR heterodimers are able to substitute for LXR alpha in mediating this retinoid response. We provide evidence that the retinoid response on the LXRE is the result of a unique interaction between LXR alpha and endogenous RXR, which, unlike in the RXR/RAR heterodimer, makes RXR competent to respond to retinoids. Thus, the interaction with LXR alpha shifts RXR from its role described previously as a silent, DNA-binding partner to an active ligand-binding subunit in mediating retinoid responses through target genes defined by LXREs.

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RXRβ: A coregulator that enhances binding of retinoic acid, thyroid hormone, and vitamin D receptors to their cognate response elements

1991-12-01

Victor C. Yu , Claude Delsert , Bogi Andersen +7 more

Characterization of three RXR genes that mediate the action of 9-cis retinoic acid.

1992-03-01

David J. Mangelsdorf , Uwe Borgmeyer , R A Heyman +5 more

An understanding of the differences and similarities of the retinoid X receptor (RXR) and retinoic acid receptor (RAR) systems requires knowledge of the diversity of their family members, their patterns … An understanding of the differences and similarities of the retinoid X receptor (RXR) and retinoic acid receptor (RAR) systems requires knowledge of the diversity of their family members, their patterns of expression, and their pharmacological response to ligands. In this paper we report the isolation of a family of mouse RXR genes encoding three distinct receptors (RXR alpha, beta, and gamma). They are closely related to each other in their DNA- and ligand-binding domains but are quite divergent from the RAR subfamily in both structure and ligand specificity. Recently, we demonstrated that all-trans retinoic acid (RA) serves as a "pro-hormone" to the isomer 9-cis RA, which is a high-affinity ligand for the human RXR alpha. We extend those findings to show that 9-cis RA is also "retinoid X" for mouse RXR alpha, beta, and gamma. Trans-activation analyses show that although all three RXRs respond to a variety of endogenous retinoids, 9-cis RA is their most potent ligand and is up to 40-fold more active than all-trans RA. Northern blot and in situ hybridization analyses define a broad spectrum of expression for the RXRs, which display unique patterns and only partially overlap themselves and the RARs. This study suggests that the RXR family plays critical roles in diverse aspects of development, from embryo implantation to organogenesis and central nervous system differentiation, as well as in adult physiology.

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TISSUE CHANGES FOLLOWING DEPRIVATION OF FAT-SOLUBLE A VITAMIN

1925-12-01

S. B. Wolbach , Percy R. Howe

The specific tissue changes which follow the deprivation of fat-soluble vitamin A in albino white rats and in the human concerns epithelial tissues. This effect is the substitution of stratified … The specific tissue changes which follow the deprivation of fat-soluble vitamin A in albino white rats and in the human concerns epithelial tissues. This effect is the substitution of stratified keratinizing epithelium for normal epithelium in various parts of the respiratory tract, alimentary tract, eyes, and paraocular glands and the genitourinary tract. We have described the morphological sequences which clearly show that the replacement of epithelium arises from focal proliferation of cells arising from the original epithelium and not by differentiation or change of preexisting cells. Young rats respond to the deficiency more promptly than adults. Growth activity of epithelium is not diminished. On the contrary, there is convincing evidence that it is greatly augmented. In a few of our animals the behavior of the replacing epithelium in respect to numbers of mitotic figures and response on the part of connective tissue and blood vessels suggests the acquisition of neoplastic properties. While the epitheliums which are the seats of these changes are largely of covering types, glandular epithelium is involved, specifically in the paraocular glands and salivary glands. It is highly probable also that the epithelium of gland ducts, respiratory mucosa, and genitourinary tract have secretory functions so that we conclude that the deficiency results in loss of specific (chemical) functions of the epitheliums concerned, while the power of growth becomes augmented. Explanation for the substitution of a chemically inactive (nonsecretory) epithelium, common in type for all locations, remains a matter of speculation. We can only speculate also in regard to the absence of change in the epithelium of such organ as the liver, parenchyma of the kidney, stomach, and intestines. The significance of the order or sequence in which different organs exhibit this change has not been determined. In general the respiratory mucosa in nares, trachea, and bronchi respond first, then the salivary glands, eye, genitourinary tract, then paraocular glands and pancreas, although as has been noted there are exceptions to this order. Our studies show that the mitochondrial apparatus is not primarily affected. Study of individual cells indicates that the first morphological evidence of avitaminosis will be found in the nucleus. We have not devoted sufficient study to be certain, but an increase of chromatin and in some instances in size of nucleoli are early morphological manifestations. Other important effects of fat-soluble A deficiency are atrophy of glandular organs, emaciation, localized edema of testes, submaxillary gland, and connective tissue structures of the lungs and focal myocardial lesions. From our own limited experience with rats fed on a water-soluble B deficient diet and from work by Cramer, Drew, and Mottram, the loss of fat in water-soluble B deficiency is as great, if not greater than in vitamin A deuciency, so that tor tne present we assume that this is not a specific manifestation of any one avitaminosis. The same applies to glandular atrophy. Both of these effects probably concern the nutrition as a whole and may be ascribed to inanition. The occurrence of transient edema in testes and salivary gland coinciding with a period of maximum atrophic change, suggests the hypothesis that this edema is the result of failure of epithelium to utilize transported material, which leads further to the hypothesis that the capillaries of these organs are differentiated in regard to permeability to the respective materials utilized by the cells. It would seem that in the case of the testis we have a unique instance of complete atrophy producible at will without impairment of circulation and supporting tissues. This phenomenon may possibly be followed with advantage in the study of the mechanism of edema. Vascularization of the cornea, as we have shown it to be independent of infection, must be a physiological response to the increased demands of the rapidly growing epithelium which has replaced the corneal epithelium. We have assumed throughout this work that the diet on which we kept our animals was deficient in respect to a single substance or group of substances having similar physiological properties, designated by the term fat-soluble vitamin A. Whether or not more than one so called vitamin or accessory substance was missing in the diet we employed does not affect the theoretical importance of the morphological results. Work by Evans and Bishop would indicate that other factors affecting fertility in addition to the so called antixerophthalmic or vitamin A factor may have been missing. Our own experience leads us to believe the specific effects we have described upon epithelial tissues were in all probability due to withdrawal of a single factor. We have shown how these effects, that is the replacement of uterine epithelium by keratinizing epithelium can account for sterility in the female. Whether or not the atrophy of the testis is due to the same factor remains to be proved, but presumptive evidence is strong that this is the case. The study of the reverse changes that follow in the rapid amelioration when the rats are restored to an adequate diet has been begun and will be reported later. We have shown that the substitution of keratinizing epithelium in all locations is not secondary to infections, and presumably is a primary effect of the withdrawal of factors essential for the chemical activities or maintenance of differentiation of the epitheliums concerned. It is, of course, possible that the phenomenon is produced in a roundabout way in that it may be secondary to the effects of the avitaminosis upon the metabolism of tissue-sustaining substances. This possibility is supported by the cessation of growth of the skeleton and teeth, although we know that other avitaminoses produce retardation of growth.

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Retinoic Acid and Arsenic Trioxide for Acute Promyelocytic Leukemia

2013-07-10

Francesco Lo‐Coco , Giuseppe Avvisati , Marco Vignetti +7 more

All-trans retinoic acid (ATRA) with chemotherapy is the standard of care for acute promyelocytic leukemia (APL), resulting in cure rates exceeding 80%. Pilot studies of treatment with arsenic trioxide with … All-trans retinoic acid (ATRA) with chemotherapy is the standard of care for acute promyelocytic leukemia (APL), resulting in cure rates exceeding 80%. Pilot studies of treatment with arsenic trioxide with or without ATRA have shown high efficacy and reduced hematologic toxicity.We conducted a phase 3, multicenter trial comparing ATRA plus chemotherapy with ATRA plus arsenic trioxide in patients with APL classified as low-to-intermediate risk (white-cell count, ≤10×10(9) per liter). Patients were randomly assigned to receive either ATRA plus arsenic trioxide for induction and consolidation therapy or standard ATRA-idarubicin induction therapy followed by three cycles of consolidation therapy with ATRA plus chemotherapy and maintenance therapy with low-dose chemotherapy and ATRA. The study was designed as a noninferiority trial to show that the difference between the rates of event-free survival at 2 years in the two groups was not greater than 5%.Complete remission was achieved in all 77 patients in the ATRA-arsenic trioxide group who could be evaluated (100%) and in 75 of 79 patients in the ATRA-chemotherapy group (95%) (P=0.12). The median follow-up was 34.4 months. Two-year event-free survival rates were 97% in the ATRA-arsenic trioxide group and 86% in the ATRA-chemotherapy group (95% confidence interval for the difference, 2 to 22 percentage points; P<0.001 for noninferiority and P=0.02 for superiority of ATRA-arsenic trioxide). Overall survival was also better with ATRA-arsenic trioxide (P=0.02). As compared with ATRA-chemotherapy, ATRA-arsenic trioxide was associated with less hematologic toxicity and fewer infections but with more hepatic toxicity.ATRA plus arsenic trioxide is at least not inferior and may be superior to ATRA plus chemotherapy in the treatment of patients with low-to-intermediate-risk APL. (Funded by Associazione Italiana contro le Leucemie and others; ClinicalTrials.gov number, NCT00482833.).

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Induction of differentiation of the human promyelocytic leukemia cell line (HL-60) by retinoic acid.

1980-05-01

T. R. Breitman , Stuart E. Selonick , SJ Collins

The HL-60 cell line, derived from a patient with acute promyelocytic leukemia, proliferates continuously in suspension culture and consists predominantly (greater than 90%) of promyelocytes. These cells can be induced … The HL-60 cell line, derived from a patient with acute promyelocytic leukemia, proliferates continuously in suspension culture and consists predominantly (greater than 90%) of promyelocytes. These cells can be induced to differentiate to morphologically and functionally mature granulocytes by incubation with a wide variety of compounds, including butyrate and hypoxanthine and polar planar compounds such as dimethyl sulfoxide and hexamethylene bisacetamide. We have now found that retinoic acid (all-trans-retinoic acid) induces differentiation (as measured morphologically and by the ability to reduce nitroblue tetrazolium) of HL-60 at concentrations as low as 1 nM. Maximal differentiation (approximately 90%) occurs at 1 micro M, a concentration 1/500th to 1/160,000th the concentrations of butyrate (0.5 mM) and dimethyl sulfoxide (160 mM) that promote a similar increase in differentiation. Continuous exposure to retinoic acid is necessary for optimal differentiation, with the percentage of mature cells in the culture directly related to the length of time of exposure to retinoic acid. Retinoic acid and 13-cis-retinoic acid are equally effective in inducing differentiation of HL-60. Retinol (vitamin A), retinal, and retinyl acetate are approximately 1/1000th less potent. This study suggests that retinoids could provide a therapeutic tool in the treatment of acute myeloid leukemia, a disease that has been looked upon as primarily involving a block in myeloid differentiation, and indicates that retinoids, in addition to their well-characterized involvement in epithelial cell differentiation, may also be involved in the differentiation of certain hematopoietic cells.

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Crystal structure of the RAR-γ ligand-binding domain bound to all-trans retinoic acid

1995-12-01

Jean‐Paul Renaud , Natacha Rochel , Marc Ruff +4 more

Use of Arsenic Trioxide (As2O3 ) in the Treatment of Acute Promyelocytic Leukemia (APL): II. Clinical Efficacy and Pharmacokinetics in Relapsed Patients

1997-05-01

Zhi-Xiang Shen , Guoqiang Chen , Jian-Hua Ni +7 more

AP-1 subunits: quarrel and harmony among siblings

2004-11-24

Jochen Heß , Peter Angel , Marina Schorpp‐Kistner

The AP-1 transcription factor is mainly composed of Jun, Fos and ATF protein dimers. It mediates gene regulation in response to a plethora of physiological and pathological stimuli, including cytokines, … The AP-1 transcription factor is mainly composed of Jun, Fos and ATF protein dimers. It mediates gene regulation in response to a plethora of physiological and pathological stimuli, including cytokines, growth factors, stress signals, bacterial and viral infections, as well as oncogenic stimuli. Studies in genetically modified mice and cells have highlighted a crucial role for AP-1 in a variety of cellular events involved in normal development or neoplastic transformation causing cancer. However, emerging evidence indicates that the contribution of AP-1 to determination of cell fates critically depends on the relative abundance of AP-1 subunits, the composition of AP-1 dimers, the quality of stimulus, the cell type and the cellular environment. Therefore, AP-1-mediated regulation of processes such as proliferation, differentiation, apoptosis and transformation should be considered within the context of a complex dynamic network of signalling pathways and other nuclear factors that respond simultaneously.

Complete Remission after Treatment of Acute Promyelocytic Leukemia with Arsenic Trioxide

1998-11-05

Steven L. Soignet , P. Maslak , Zhugang Wang +7 more

Two reports from China have suggested that arsenic trioxide can induce complete remissions in patients with acute promyelocytic leukemia (APL). We evaluated this drug in patients with APL in an … Two reports from China have suggested that arsenic trioxide can induce complete remissions in patients with acute promyelocytic leukemia (APL). We evaluated this drug in patients with APL in an attempt to elucidate its mechanism of action.

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Differentiation Therapy of Acute Promyelocytic Leukemia with Tretinoin (All-trans-Retinoic Acid)

1991-05-16

Raymond P. Warrell , Stanley R. Frankel , Wilson H. Miller +7 more

Patients with acute promyelocytic leukemia have a characteristic (15;17) translocation, with a breakpoint on chromosome 17 in the region of the retinoic acid receptor—alpha (RAR-α). Since this receptor has been … Patients with acute promyelocytic leukemia have a characteristic (15;17) translocation, with a breakpoint on chromosome 17 in the region of the retinoic acid receptor—alpha (RAR-α). Since this receptor has been shown to be involved with growth and differentiation of myeloid cells in vitro, and since recent clinical studies have reported that tretinoin (all-trans-retinoic acid) induces complete remission in patients with acute promyelocytic leukemia, we studied the effects of tretinoin on cellular maturation and molecular abnormalities in patients undergoing the induction of remission with this agent.

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All-<i>trans</i>-Retinoic Acid in Acute Promyelocytic Leukemia

1997-10-09

Martin S. Tallman , Janet W. Andersen , Charles A. Schiffer +7 more

All-trans-retinoic acid induces complete remission in acute promyelocytic leukemia. However, it is not clear whether induction therapy with all-trans-retinoic acid is superior to chemotherapy alone or whether maintenance treatment with … All-trans-retinoic acid induces complete remission in acute promyelocytic leukemia. However, it is not clear whether induction therapy with all-trans-retinoic acid is superior to chemotherapy alone or whether maintenance treatment with all-trans-retinoic acid improves outcome.

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Retinoic Acid Embryopathy

1985-10-03

Edward J. Lammer , Diane T. Chen , Richard M. Hoar +7 more

Retinoic acid, an analogue of vitamin A, is known to be teratogenic in laboratory animals and has recently been implicated in a few clinical case reports. To study the human … Retinoic acid, an analogue of vitamin A, is known to be teratogenic in laboratory animals and has recently been implicated in a few clinical case reports. To study the human teratogenicity of this agent, we investigated 154 human pregnancies with fetal exposure to isotretinoin, a retinoid prescribed for severe recalcitrant cystic acne. The outcomes were 95 elective abortions, 26 infants without major malformations, 12 spontaneous abortions, and 21 malformed infants. A subset of 36 of the 154 pregnancies was observed prospectively. The outcomes in this cohort were 8 spontaneous abortions, 23 normal infants, and 5 malformed infants. Exposure to isotretinoin was associated with an unusually high relative risk for a group of selected major malformations (relative risk = 25.6; 95 per cent confidence interval, 11.4 to 57.5). Among the 21 malformed infants we found a characteristic pattern of malformation involving craniofacial, cardiac, thymic, and central nervous system structures. The malformations included microtia/anotia (15 infants), micrognathia (6), cleft palate (3), conotruncal heart defects and aortic-arch abnormalities (8), thymic defects (7), retinal or optic-nerve abnormalities (4), and central nervous system malformations (18). The pattern of malformation closely resembled that produced in animal studies of retinoid teratogenesis. It is possible that a major mechanism of isotretinoin teratogenesis is a deleterious effect on cephalic neural-crest cell activity that results in the observed craniofacial, cardiac, and thymic malformations.

All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical results [see comments]

1990-11-01

Sylvie Castaigné , Christine Chomienne , MT Daniel +4 more

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A transcriptional co-repressor that interacts with nuclear hormone receptors

1995-10-01

J. Don Chen , Ronald M. Evans

Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions.

2001-11-20

Ann‐Lii Cheng , Chih‐Hung Hsu , Jen‐Kou Lin +7 more

Curcumin (diferuloylmethane), a yellow substance from the root of the plant Curcuma longa Linn., has been demonstrated to inhibit carcinogenesis of murine skin, stomach, intestine and liver. However, the toxicology, … Curcumin (diferuloylmethane), a yellow substance from the root of the plant Curcuma longa Linn., has been demonstrated to inhibit carcinogenesis of murine skin, stomach, intestine and liver. However, the toxicology, pharmacokinetics and biologically effective dose of curcumin in humans have not been reported. This prospective phase-I study evaluated these issues of curcumin in patients with one of the following five high-risk conditions: 1) recently resected urinary bladder cancer; 2) arsenic Bowen's disease of the skin; 3) uterine cervical intraepithelial neoplasm (CIN); 4) oral leucoplakia; and 5) intestinal metaplasia of the stomach. Curcumin was taken orally for 3 months. Biopsy of the lesion sites was done immediately before and 3 months after starting curcumin treament. The starting dose was 500 mg/day. If no toxicity > or = grade II was noted in at least 3 successive patients, the dose was then escalated to another level in the order of 1,000, 2,000, 4,000, 8,000, and 12,000 mg/day. The concentration of curcumin in serum and urine was determined by high pressure liquid chromatography (HPLC). A total of 25 patients were enrolled in this study. There was no treatment-related toxicity up to 8,000 mg/day. Beyond 8,000 mg/day, the bulky volume of the drug was unacceptable to the patients. The serum concentration of curcumin usually peaked at 1 to 2 hours after oral intake of crucumin and gradually declined within 12 hours. The average peak serum concentrations after taking 4,000 mg, 6,000 mg and 8,000 mg of curcumin were 0.51 +/- 0.11 microM, 0.63 +/- 0.06 microM and 1.77 +/- 1.87 microM, respectively. Urinary excretion of curcumin was undetectable. One of 4 patients with CIN and 1 of 7 patients with oral leucoplakia proceeded to develop frank malignancies in spite of curcumin treatment. In contrast, histologic improvement of precancerous lesions was seen in 1 out of 2 patients with recently resected bladder cancer, 2 out of 7 patients of oral leucoplakia, 1 out of 6 patients of intestinal metaplasia of the stomach, I out of 4 patients with CIN and 2 out of 6 patients with Bowen's disease. In conclusion, this study demonstrated that curcumin is not toxic to humans up to 8,000 mg/day when taken by mouth for 3 months. Our results also suggest a biologic effect of curcumin in the chemoprevention of cancer.

RETINOL DISPERSION IN THE FORM OF HYDROGEL FOR DERMAL DELIVERY

2025-06-25

Florentina Lavinia Matei , Bogdan Alexandru Sava , Andreea-Iuliana Miron +6 more | Studia Universitatis Babeș-Bolyai Chemia

Comparison of induction with arsenic trioxide or chemotherapy in a real-world cohort of patients with high-risk acute promyelocytic leukemia

2025-06-24

Delphine Lebon , Audrey Da Rocha , Bruno Cassinat +7 more | Leukemia

Acute Promyelocytic Leukemia Harboring STAT3::RARA Fusion: Current Summary

2025-06-24

Zhan Su , Haidong Zhu | Bratislavské lekárske listy/Bratislava medical journal

Evaluating Outcomes in Acute Promyelocytic Leukemia Patients Treated with All-Trans-Retinoic Acid and Arsenic Trioxide

2025-06-23

Girish Kamat , Girish Balikai , Deepak Goni +1 more | Indian Journal of Hematology and Blood Transfusion

Tretinoin

2025-06-21

| Reactions Weekly

The protective role of Agrin and CAF22 in hypertensive nephropathy

2025-06-20

Chunhui Yuan , Peng Zhang , Zhongping Zhan +5 more | International Immunopharmacology

Successful management of acute promyelocytic leukemia in the third trimester of pregnancy: a case report and review of the literature

2025-06-18

Sirichai Puttirangsan , B. Prasertkanchana , Natnipa Parapob +2 more | Frontiers in Hematology

Acute promyelocytic leukemia (APL) during pregnancy is an exceptionally rare occurrence with high maternal and fetal mortality rates, requiring a highly tailored approach to therapy. We report a case of … Acute promyelocytic leukemia (APL) during pregnancy is an exceptionally rare occurrence with high maternal and fetal mortality rates, requiring a highly tailored approach to therapy. We report a case of a patient diagnosed with APL during the third trimester of pregnancy who initially presented with spontaneous ecchymoses. Treatment was initiated with all-trans retinoic acid (ATRA) and a modified dose of idarubicin, leading to a rapid correction of the coagulopathy and a complete remission of the APL. The patient subsequently underwent induced labor, resulting in an uncomplicated vaginal delivery without significant hemorrhage and no evidence of embryopathy in the neonate. To date, no published reports of successful deliveries in patients with APL have been documented in Thailand. This case highlights how a multidisciplinary approach involving obstetricians, hematologists, and neonatologists ensured both maternal survival and optimal neonatal outcomes.

Protein-bound cisplatin could exhibit an efficient antitumor effect in vivo

2025-06-17

Nana Cristina Amorim Matsuo , Hidenori Ando , Haruka Takata +1 more | Journal of Pharmaceutical Sciences

Author Correction: Absence of CD36 alters systemic vitamin A homeostasis

2025-06-16

Michael J. Trites , Maria Febbraio , Robin D. Clugston | Scientific Reports

Exploring the inhibitory effects of Brassica juncea extract and sinigrin on lipid accumulation in BPA-Induced 3T3-L1 cells via the glucocorticoid receptor and peroxisome proliferator-activated receptor-γ pathways

2025-06-13

Ji‐Hyun Im , Geon Oh , Xiaolu Fu +5 more | Food Science and Biotechnology

Abstract P2-04-10: ARL3 Promotes Hormone Receptor Positive Breast Cancer Progression and Tamoxifen Resistance through ERα Stablization

2025-06-13

Li Han , Yang Liu , Zehao Cai +4 more | Clinical Cancer Research

Abstract Background: Hormone Receptor Positive (HR+) breast cancer is predominantly managed with endocrine therapies that target the Estrogen Receptor Alpha (ERα), a key mediator of estrogen's role in promoting tumor … Abstract Background: Hormone Receptor Positive (HR+) breast cancer is predominantly managed with endocrine therapies that target the Estrogen Receptor Alpha (ERα), a key mediator of estrogen's role in promoting tumor growth. However, the emergence of endocrine resistance poses a significant clinical challenge, limiting the efficacy of these treatments and impeding optimal patient outcomes. Understanding the mechanisms behind ERα's importance and the development of resistance is crucial for advancing therapeutic strategies against HR+ breast cancer. Methods: In our study, we utilized the GEO database to identify ADP-Ribosylation Factor-Like GTPase 3 (ARL3) as a gene associated with tamoxifen resistance in HR+ breast cancer. We constructed cell lines with ARL3 knockout and overexpression to assess the impact of ARL3 on cell proliferation, migration, and tamoxifen sensitivity. RNA sequencing (RNA-seq) and liquid chromatography-mass spectrometry (LC/MS) were employed to demonstrate the influence of ARL3 knockout on downstream ERα pathways. Furthermore, co-immunoprecipitation (CO-IP), immunofluorescence and Western blot (WB) assays confirmed the role of ARL3 in the ubiquitination and degradation pathway of ERα. Results: In our analysis of TCGA breast cancer subtypes, we also observed that ARL3 is highly expressed in luminal breast cancer. Additionally, our collection of breast cancer tissue mRNA and immunohistochemistry data revealed that ARL3 expression is elevated in HR+ breast cancer, indicating a correlation with estrogen receptors. We found that ARL3 promotes the proliferation and migration of HR+ breast cancer. Furthermore, overexpression of ARL3 was associated with reduced sensitivity to tamoxifen, and in vivo tumorigenesis in nude mice showed that tumor volume and weight were significantly decreased compared to the control group. To investigate the underlying mechanisms, RNA-seq analysis of ARL3 knockout and control groups revealed a pronounced inhibition of the MYC pathway. Western blot (WB) validation confirmed that ARL3 knockout suppresses the expression of downstream pathways of ERα. Our data suggest that the association between ARL3 and ERα primarily occurs in the cytoplasm, mainly binding to the ligand-binding domain (LBD) of ERα, which is consistent with ARL3 not being recruited to the promoters occupied by ERα. We also discovered that the ARL3/ERα cascade promotes mitochondrial autophagy to enhance mitochondrial oxidative phosphorylation. In summary, our study establishes a non-genomic mechanism whereby ARL3 controls the transcription of estrogen-dependent genes associated with breast cancer cell proliferation by stabilizing ERα levels. Conclusion: In our study, we posit that ADP-ribosylation factor-like GTPase 3 (ARL3) exerts a pivotal influence on the proliferative capacity, metastatic potential, and responsiveness to endocrine therapies in hormone receptor-positive (HR+) breast cancer. ARL3 modulates the stability of estrogen receptor alpha (ERα), thereby regulating the activation of downstream signaling cascades and the mitochondrial functionality within neoplastic cells. Our findings suggest that ARL3 represents a promising therapeutic target for HR+ breast cancer. We envision that in-depth investigation into the molecular underpinnings of ARL3's role could pave the way for the development of innovative pharmacological agents capable of overcoming endocrine resistance in patients, ultimately enhancing their clinical outcomes and survival rates. Citation Format: Han Li, Yang Liu, Zehao Cai, Dan Shu, Yang Peng, Kang Li, Shengchun Liu. ARL3 Promotes Hormone Receptor Positive Breast Cancer Progression and Tamoxifen Resistance through ERα Stablization [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-04-10.

Abstract PS9-07: Epigenomic Characterization of ER Transcriptional Activation via Liquid Biopsy

2025-06-13

Jonathan A. Beagan , Suzanne E. Wardell , Travis Clark +7 more | Clinical Cancer Research

Abstract Background: Endocrine therapies (ET) are a cornerstone treatment for estrogen receptor-positive (ER+) breast cancer (BC). ET’s efficacy depends on the transcriptional addiction of the cancer cells to estrogen receptor … Abstract Background: Endocrine therapies (ET) are a cornerstone treatment for estrogen receptor-positive (ER+) breast cancer (BC). ET’s efficacy depends on the transcriptional addiction of the cancer cells to estrogen receptor signaling, for which there is no current clinical test. ER IHC and ESR1 mutations are insufficient proxies for ER transcriptional dependency. A blood-based biomarker for dynamic measurement of the ER transcriptional dependency of a tumor would greatly improve our ability to identify patients who would most benefit from continued ET. Methods: We profiled key epigenomic determinants of ER transcriptional activity in a broad array of ER+ BC cell lines, and then translated the resulting epigenomic signature into a form assayable in 1mL of plasma from BC patients. First, we profiled the epigenome of 8 breast cancer cell lines (MCF7, T47D, BT483, CAMA1, HCC1428, ZR-75-1, MDA-MB-361) in estrogen depleted media and in the presence of physiologically relevant levels of estradiol (E2, 0.1nM). Using ChIP-seq for histone modifications associated with active promoters and enhancers paired with enrichment-based DNA methylation we identified the epigenomic loci most associated with response to E2. The concurrent plating and treatment of these cell lines makes this a unique resource for the identification of enhancers, promoters, and DNA methylation marks associated with transcriptional response to estrogen signaling. We then employed the Precede multi-analyte liquid biopsy assay, which profiles these same epigenomic features from 1mL of patient plasma and used proprietary computational methods to combine information across analytes to create a patient-specific ER activity quantification algorithm robust to varying levels of circulating tumor DNA fraction (ctDNA%). We analyzed plasma from 38 patients with ER+ metastatic BC seen at the OHSU Knight Cancer Institute who had blood drawn within 1 week of tumor biopsy with ER and HER2 IHC. Additionally, we profiled 48 patient samples with the same characteristics sourced from commercial biobanks. Results: We identified an epigenomic signature that profiles ER activity in patient plasma samples. Through a paired genome-wide analysis of all cell lines’ response to E2, we identified 2320 E2-upregulated enhancers, 334 E2-upregulated promoters, and—intriguingly—0 DNA methylation loci that responded to E2 modulation. E2 responsive enhancers and promoters are linked to genes associated with estrogen response, cell cycle, and epithelial to mesenchymal transition. Many of these sites are located adjacent to known ESR1, FOXA1, and GATA3 binding sites. Computational refinement and aggregation of a subset of the E2-induced enhancers enabled the creation of an ER activity score that can be assayed in patient plasma and is robust to clinically relevant levels of ctDNA%. Patients with ER+ tumors displayed higher ER activity scores compared to patients with ER- tumors, and scores were consistently high for patients with ESR1 mutations. This plasma-based ER activity score is highly correlated with previously published RNA-based ER activity scores (Guan et al. 2019) which require biopsy tissue. Conclusions: ER transcriptional pathway activation correlates with changes to the epigenome that are detectable via Precede multi-analyte liquid biopsy assay, enabling a measurement of breast cancer dependence on endocrine signaling from 1mL of plasma through an ER activity score. This ER activity score is biologically interpretable and correlates with previous RNA-seq based predictors of ER activity. While ESR1 mutant patients score consistently high, a subset of ESR1 wildtype patients also demonstrate high ER activity scores, implying a potentially expanded patient population for treatment with novel anti-endocrine agents such as SERDs. Citation Format: Jonathan Beagan, Suzanne Wardell, Travis Clark, Justin Finkle, Anthony D’Ippolito, Mike Zhong, Jamey Guess, Kristian Cibulskis, Aparna Gorthi, Tyrone Tamakloe, Charlene O'Brien, Baovy Tran, Sarah Kieft, Mary McGillicuddy, Jayne M Stommel, Allison L Creason, Julian Egger, Gordon B Mills, Corrie Painter, Matthew Eaton, Donald McDonnell, J. Carl Barrett. Epigenomic Characterization of ER Transcriptional Activation via Liquid Biopsy [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr PS9-07.

Abstract P5-06-27: OXTR inhibits breast cancer cell invasion and metastasis by regulating the post-translational modification of the COL1A1 protein to accelerate its degradation through the lysosomal pathway

2025-06-13

Qing Shao | Clinical Cancer Research

Abstract Background: The oxytocin receptor (OXTR) is a hormone receptor that is highly expressed in the breast, and its expression is significantly reduced when breast tissue becomes cancerous. In addition … Abstract Background: The oxytocin receptor (OXTR) is a hormone receptor that is highly expressed in the breast, and its expression is significantly reduced when breast tissue becomes cancerous. In addition to serving as a receptor for receiving stimulation from hormones, neurotransmitters, and growth factors to mediate their effects, the biological function and molecular mechanism of OXTR itself in breast cancer (BrCa) are still unclear. Methods: Using quantitative PCR (qRT-PCR), Western blot, immunohistochemistry (IHC), and public database analysis, the expression of OXTR in BrCa adjacent normal tissues, BrCa tissues, and metastatic tissues, as well as its correlation with prognosis were evaluated. The migration and invasion functions of OXTR were analyzed by wound-healing and transwell assays in vitro. Lung metastatic tumor models were used to study the invasion and metastasis of OXTR in vivo. RNA-seq, Western blot, immunofluorescence (IF), immunoprecipitation (IP) and Co-IP were further applied to determine the detailed mechanism. Results: OXTR is downregulated in BrCa tissues, especially in distant metastases. Patients with lower OXTR expression have worse overall survival (OS) and distant metastasis-free survival (DMFS). In functional experiments, overexpression of OXTR suppresses BrCa cell migration, invasion and metastasis in vitro and in vivo. Conversely, knockdown of OXTR increased BrCa cell spreading. OXTR functions by inhibiting the expression of the oncoprotein collagen type I alpha 1 chain (COL1A1), which is closely associated with epithelial-mesenchymal transition (EMT). The mechanism is mainly that OXTR causes the decrease of COL1A1 protein phosphorylation and the increase of O-GlcNAcylation by down-regulating CDK1. However, O-GlcNAcylated COL1A1 is unstable and can be easily degraded by the lysosomal pathway. Conclusions: This study extends the ligand-independent function of OXTR in BrCa and highlights the role of OXTR in suppressing invasion and metastasis of BrCa cells, as well as predicting prognosis. This study elucidates the specific mechanism by which OXTR accelerates the degradation of COL1A1 protein by regulating its post-translational modifications (PTMs), thereby affecting the malignant progression of cancer cell metastasis. These findings suggest that OXTR may serve as a marker to predict the metastatic potential or prognosis of BrCa. Citation Format: Qing Shao. OXTR inhibits breast cancer cell invasion and metastasis by regulating the post-translational modification of the COL1A1 protein to accelerate its degradation through the lysosomal pathway [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-06-27.

Abstract P2-02-08: Chromosome 8q gain-related transcription factor MYBL1 is a critical regulator in triple-negative breast cancer

2025-06-13

Akihiro Fujimoto , Kazuhiro Ikeda , Keiichi Kinowaki +4 more | Clinical Cancer Research

Abstract Chromosome arm-level aneuploidies (CAAs) are a common consequence of genomic instability during the evolution of solid tumor and often associated with metastasis and therapy resistance. In breast cancer, chromosome … Abstract Chromosome arm-level aneuploidies (CAAs) are a common consequence of genomic instability during the evolution of solid tumor and often associated with metastasis and therapy resistance. In breast cancer, chromosome arms 1q and 8q are the frequent amplified regions for CAAs. This study aims to investigate whether critical genes amplified in genomic regions with CAAs contribute to the pathophysiology in triple-negative breast cancer (TNBC). We established multiple long-term culturable TNBC patient-derived cells (PDCs) using spheroid culture technique, which is favorable for the enrichment of cell population with cancer stemness. We performed a genome-wide chromatin immunoprecipitation study for histone H3K27ac and super-enhancer analysis in these TNBC PDCs and cell lines. Super-enhancer analysis revealed that 8q is a substantial chromosomal region with a high density of super-enhancers. Among genes in the vicinity of 8q super-enhancers, we identified that MYB proto-oncogene like 1 (MYBL1) is a transcription factor with high abundance in TNBC PDCs as well as in basal-like BT549 cells. In TCGA breast cancer database, 8q gain is a common genomic feature in MYBL1 gene-amplified breast cancer tissues and MYBL1 expression is substantially correlated with 8q-related genes and proliferation-related genes like MKI67 and BUB1. In TNBC PDCs and cell lines, we showed that MYBL1-specific siRNAs significantly repressed TNBC cell proliferation and migration. RNA sequencing analysis in TNBC cells revealed that MYBL1 silencing substantially downregulated genes involved in the transcription machinery such as nuclear envelope, chromatin dynamics, and DNA replication. In immunohistochemical analysis of clinical TNBC tissues from a Japanese cohort, we showed that a positive MYBL1 immunoreactivity (IR) was significantly associated with shorter disease-free survival (DFS). Among candidate MYBL1 targets, we demonstrated that NCAPH, a subunit of condensin I complex, was a prognostic factor for patients with TNBC based on the immunohistochemistry of clinical TNBC tissues. Notably, patients with double IR positivity for MYBL1 and NCAPH showed shorter DFS than those with MYBL1 or NCAPH positivity alone. MYBL1 has been characterized as an essential transcriptional regulator in male meiosis and in female mammary gland development. Our findings indicate that MYBL1 plays an essential role in the pathophysiology for advanced breast cancers such as TNBC, and MYBL1 and its downstream genes can be potential diagnostic and therapeutic targets for the disease. Citation Format: Akihiro Fujimoto, Kazuhiro Ikeda, Keiichi Kinowaki, Hidetaka Kawabata, Akihiko Osaki, Satoshi Inoue, Kuniko Horie. Chromosome 8q gain-related transcription factor MYBL1 is a critical regulator in triple-negative breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-02-08.

Abstract P1-05-22: Targeting human Endoplasmic reticulum oxidoreductin 1-Lα in novel therapy for triple negative breast cancer

2025-06-13

Asaka Wada , Yoshihiko Hirohashi , Goro Kutomi +3 more | Clinical Cancer Research

Abstract Background: Triple negative breast cancer (TN breast cancer) has a poor prognosis and few therapeutic targets, and the development of novel therapies is desirable.Human endoplasmic reticulum oxidoreductin 1-Lα (hERO1-Lα) … Abstract Background: Triple negative breast cancer (TN breast cancer) has a poor prognosis and few therapeutic targets, and the development of novel therapies is desirable.Human endoplasmic reticulum oxidoreductin 1-Lα (hERO1-Lα) is an oxidase that exists in the endoplasmic reticulum and its expression is augmented under hypoxia. hERO1-Lα has a role in the formation of disulfide bonds of secreted proteins and cell-surface proteins. We reported that hERO1-Lα is present in high levels in various types of tumors, and is a poor prognostic factor of TN breast cancer. We have focused on hERO1-Lα as a novel target molecule in TN breast cancer. In this study, we demonstrated that hERO1-Lα expression is involved in epithelial to mesenchymal transition (EMT), which is a process related to cancer metastasis and invasion, and analyzed its molecular mechanism. In addition, we investigated the effect of ERO1-Lα inhibitor (ERO1-Lα-I ) on distant metastasis inhibition and anti-tumor effect for clinical application. Materials and Methods: We generated MDA-MB-231 cells with hERO1-Lα knockdown (KD) using shRNA against hERO1-Lα, and with ERO1-Lα overexpression(OE)transfected with human hERO1-Lα cDNA. EMT changes in cells were analyzed by observation of cell morphology and western blotting (WB), and the same analysis was performed with the addition of ERO1-Lα-I (EN460). Cell motility was evaluated by scratch assay and invasive ability was evaluated by cell invasion assay. Since hERO1-Lα regulates the production of secreted proteins, we searched for EMT-related factors by comparing the results of cytokine arrays and ELISA using culture supernatants from each cell line. MCF7 with culture supernatant from OE cells was evaluated for induction of EMT using WB. The hERO1-Lα KD cells were transplanted into NOD/SCID mice and evaluated for distant metastasis. We also evaluated the anti-tumor and distant metastasis inhibitory effects of ERO1-Lα-I treatment and tumor pathology in NOD/SCID mice transplanted with TN breast cancer cell lines. Results: EMT was suppressed in the hERO1-Lα KD cells and the ERO1-Lα inhibitor-added cells in WB, while it was enhanced in the OE cells. Cell motility and invasive ability were significantly suppressed in the hERO1-Lα KD cells (p&lt;0.05).Leukemia inhibitory factor (LIF), which has been reported to be involved in EMT, was detected relatively strongly in the culture supernatant of OE cells using cytokine arrays and was considered as a candidate molecule. ELISA showed a correlation between hERO1-Lα expression and LIF secretion. MCF cells with OE cells culture supernatant containing LIF showed EMT.Lung metastases were significantly suppressed in mice transplanted with the hERO1-Lα KD cells (p&lt;0.001) . Tumor growth was significantly suppressed in mice in the ERO1-Lα inhibitor group without toxicity (p&lt;0.05) . Conclusions: hERO1-Lα suppression and hERO1-Lα inhibitors suppressed EMT of tumor cells, and LIF was identified as an EMT-related factor involving hERO1-Lα. Inhibition of hERO1-Lα suppressed distant metastasis, and addition of inhibitors showed antitumor effects. These results indicate that hERO1-Lα is involved in tumor growth and metastasis and may be a candidate for a new molecular targeted therapy for TN breast cancer. Citation Format: Asaka Wada, Yoshihiko Hirohashi, Goro Kutomi, Daisuke Kyuno, Hiroaki Shima, Toshihiko Torigoe. Targeting human Endoplasmic reticulum oxidoreductin 1-Lα in novel therapy for triple negative breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-05-22.

Abstract P4-08-21: Chlorogenic acid and cinnamaldehyde in combination demonstrate antimetastatic capabilities and induce apoptosis in MCF7 and MDA-MB-231 breast cancer cell lines via downregulation of the Akt pathway

2025-06-13

Yusuff Olayiwola , Lauren Gollahon | Clinical Cancer Research

Abstract The majority of reported breast cancer-associated deaths are directly correlated with metastatic disease. Furthermore, the nature of current metastatic cancer treatments detrimentally impacts other organ systems. Thus, there remains … Abstract The majority of reported breast cancer-associated deaths are directly correlated with metastatic disease. Furthermore, the nature of current metastatic cancer treatments detrimentally impacts other organ systems. Thus, there remains the need for more effective and safer strategies to treat metastatic breast cancer at a systemic level. Recently, more attention has been given to Natural Products as candidate anticancer approaches. This study is aimed at investigating the synergistic impact of two such natural compounds, chlorogenic acid and cinnamaldehyde (CGA:CA). We hypothesized that CGA:CA in combination, would decrease the metastatic potential of breast cancer cells by suppressing their invasive and migratory abilities induced through AKT pathway activation. We also hypothesized that apoptotic cell death would occur as a result of downregulation of Akt activation. To test this hypothesis, suppression of migration and invasion after treatment was analyzed by wound healing and Transwell Matrigel assays. FACSsort was performed to determine expression of the migration and invasion associated biomarkers fibronectin, vimentin, and EpCAM. Western blotting was used to determine the effect of the natural products on expression of phospho-AKT, E- and N-cadherin, as well as the apoptotic marker and caspase 3 and BCL2-α. Annexin V/propidium iodide fluorescence microscopy and growth curves were conducted to analyze apoptosis induction. Results showed decreased phosphorylated Akt expression upon treatment with CGA:CA. the anticancer effect of the compounds on Akt activation resulted in inhibition of metastasis, evidenced by restoration of epithelial characteristics such as increased expression of E-cadherin and EpCAM, downregulation of N-cadherin, fibronectin, vimentin and MMP-9 expression and lack of cell migration. Annexin V and Western results showed that CGA:CA significantly inhibited cancer cell growth and induced apoptosis via increased expression of caspase 3 and downregulation of Bcl2-α. Overall, the present study demonstrated that CGA:CA combination downregulated the Akt pathway, induced apoptosis, and arrested the migration and invasion of both triple-positive and triple-negative breast cancer cell lines. Citation Format: Yusuff Olayiwola, Lauren S. Gollahon. Chlorogenic acid and cinnamaldehyde in combination demonstrate antimetastatic capabilities and induce apoptosis in MCF7 and MDA-MB-231 breast cancer cell lines via downregulation of the Akt pathway [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-08-21.

Abstract P1-09-04: A Phase II study of the efficacy and safety of Perflubutane for Predicting highly Tumor Infiltrating Lymphocytes in early breast cancer

2025-06-13

Yuri Kimura | Clinical Cancer Research

Abstract Background: Tumor-infiltrating lymphocytes (TILs), a major component of the tumor immune microenvironment, reflect the host’s antitumor immune response and serve as critical biomarkers for predicting prognosis and therapeutic efficacy … Abstract Background: Tumor-infiltrating lymphocytes (TILs), a major component of the tumor immune microenvironment, reflect the host’s antitumor immune response and serve as critical biomarkers for predicting prognosis and therapeutic efficacy in breast cancer. Recently, the International Immuno-Oncology Biomarker Working Group proposed a standardized pathological evaluation method for assessing TILs, which has shown good reproducibility and concordance rates. However, due to the inherent heterogeneity of TILs within tissues and the limited sample size of pre-treatment needle biopsies in neoadjuvant chemotherapy cases, there remain challenges in establishing objectivity for clinical implementation. B-mode ultrasonography (US) allows morphological evaluation of the underlying pathology. We discovered that lymphocyte-predominant breast cancer (LPBC), characterized by abundant TILs, presents with distinctive US findings (small lobulated shape, marked hypoechoic areas, and posterior acoustic enhancement). Based on these findings, we developed a unique scoring model (TILs-US score) to predict LPBC. A multicenter retrospective study (JABTS BC-11) demonstrated that the TILs-US score significantly predicted LPBC, and the prediction accuracy was further enhanced by including tumor vascularity assessment (Area Under the Curve 0.784 vs. 0.770; sensitivity 0.93 vs. 0.83; specificity 0.57 vs. 0.55; accuracy 0.71 vs. 0.66). These results prompted a prospective evaluation of the utility of contrast-enhanced ultrasonography (CEUS), which visualizes detailed intratumoral blood flow and allows real-time qualitative and quantitative assessment of blood flow changes, to improve the accuracy of LPBC prediction in a single-arm phase II study (AppTIL study, jRCT1061220081). Methods: We performed CEUS using perflubutane on patients with early-stage breast cancer and used a new scoring model (TILs-CEUS score) incorporating the rate of contrast agent inflow to predict LPBC. The predictive accuracy of this model was compared with pathological LPBC evaluation of surgical specimens. The target sample size is 100 patients, and prospective enrollment is ongoing. Conclusion: This study aims to demonstrate the utility of CEUS as a simple method for pre-treatment evaluation of LPBC, potentially enabling its application in predicting prognosis and therapeutic efficacy of neoadjuvant chemotherapy. We intend to report the results, which may contribute to the establishment of a new radiomics-based therapeutic strategy combining tumor immune microenvironment assessment and imaging diagnostics. Citation Format: Yuri Kimura. Phase II study of the efficacy and safety of Perflubutane for Predicting highly Tumor Infiltrating Lymphocytes in early breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-09-04.

885-P: Sex-Dependent Additive Effects of Dorzagliatin and Incretin on Insulin Secretion in a Novel Mouse Model of GCK-MODY

2025-06-13

Sergio Miguel Salazar , Luis Fernando Delgadillo-Silva , PRISCILA CARAPETO +7 more | Diabetes

Introduction and Objective: Glucokinase (GK) catalyses the key regulatory step in glucose-stimulated insulin secretion. Hetero- and homozygous mutations in GCK cause maturity-onset diabetes of the young (GCK-MODY) and permanent neonatal … Introduction and Objective: Glucokinase (GK) catalyses the key regulatory step in glucose-stimulated insulin secretion. Hetero- and homozygous mutations in GCK cause maturity-onset diabetes of the young (GCK-MODY) and permanent neonatal diabetes (PNDM), respectively. Here, we develop a novel hypomorphic Gck allele to explore the utility of glucokinase activators (GKA) and glucagon-like receptor-1 (GLP-1) agonists in these diseases. Methods: Mice encoding an aberrantly spliced Gck mRNA deleted for exons 2 and 3 were generated after genomic insertion of cDNA encoding the fluorescent protein, mCardinal (GenOway, Fr). Metabolic analyses were performed using standard techniques and Ca2+ imaging, in isolated islets from animals crossed onto an Ins1Cre:GCaMP6 reporter line, on a Zeiss LSM 900 Airyscan 2 confocal microscope. Results: Homozygous GckKI/KI mice were smaller than wildtype littermates, displayed frank diabetes (fasting glucose &gt;18 mmol/L; HbA1c ~12%) and a sharp (~65%) reduction in beta cell mass. Heterozygous GckKI/+ mice were mildly glucose intolerant (HbA1c ~5.5%). GK immunoreactivity was reduced by &gt;85%, and glucose-stimulated insulin secretion was undetectable in islets from homozygous knock-in (GckKI/KI) mice. Whilst ineffective in homozygous mice, normal glucose-stimulated Ca2+ dynamics and beta cell-beta cell connectivity in GckKI/+ islets were reversed with the GKA, dorzagliatin. The GLP-1 receptor agonist exendin-4 improved glucose tolerance in male GckKI/+ mice, an action potentiated by dorzagliatin, in male but not female mice. Sex-dependent additive effects of these agents were also observed on insulin secretion in vitro. Conclusion: Combined treatment with GKA and incretin may thus be useful in GCK-MODY or GCK-PNDM, and possibly in more common forms of type 2 diabetes. Disclosure S. Salazar: None. L.F. Delgadillo Silva: None. P. Carapeto: None. K. Dakessian: None. R. Melhem: None. A. Provencher-Girard: None. G. Ostinelli: None. J. Turgeon: None. F. Migneault: None. M.O. Huising: Research Support; Thermo Fisher. G.A. Rutter: Consultant; Sun Pharmaceutical Industries Ltd.

1700-P: Sex- and Tissue-Specific Roles of X Chromosome Inactivation RNA (Xist) in Metabolic Homeostasis in Mice

2025-06-13

S. Haque , MIRZA MUHAMMAD FAHD QADIR , WEIWEI XU +2 more | Diabetes

Introduction and Objective: Xist, a long non-coding RNA essential for X chromosome inactivation (XCI) in female mammals, ensures dosage compensation of X-linked genes. Beyond XCI, Xist is implicated in immunity, … Introduction and Objective: Xist, a long non-coding RNA essential for X chromosome inactivation (XCI) in female mammals, ensures dosage compensation of X-linked genes. Beyond XCI, Xist is implicated in immunity, cell proliferation, and obesity, a major risk factor for type 2 diabetes (T2D). This study explores Xist’s role in metabolism using mouse models. Methods: We developed mouse models with tissue-specific Xist knockouts using the Cre-loxP system. Xistlox/lox mice were crossed with tissue-specific Cre recombinase-expressing transgenic mice to generate Xist knockouts in adipocytes (XistadpKO), hepatocytes (XistalbKO), and pancreatic β-cells (XistinsKO) and compared with littermate control. Male (M) and female (F) mice were fed a Western diet (WD) from 6 weeks of age for 12 weeks and body weight was tracked weekly. Glucose tolerance (GTT) and insulin tolerance (ITT) were assessed. At the end of the experiment, animals were euthanized, and fat mass (subcutaneous and epididymal WAT) was measured. Results: F XistadpKO mice developed reduced weight gain and fat mass (subcutaneous and epididymal WAT) starting at 6 weeks compared to littermate controls, alongside improved GTT. These effects were not observed in M XistadpKO mice. M XistinsKO mice showed reduced weight gain, WAT mass and improved GTT, whereas F displayed modest improvements in these parameters. M XistalbKO mice exhibited increased weight gain but no significant GTT changes in either sex. Conclusion: These findings highlight the importance of Xist’s tissue- and sex-specific roles in metabolic homeostasis under diet-induced metabolic stress. Further molecular studies are necessary to elucidate its underlying mechanisms. Disclosure S. Haque: None. M. Qadir: None. W. Xu: None. J. Kharlyngdoh: None. F. Mauvais-Jarvis: None. Funding NIH National Institute of Diabetes and Digestive and Kidney Diseases (FMJ) (DK074970); NIH National Institute of General Medical Sciences (FMJ) (P20GM152305); U.S. Department of Veterans Affairs Merit Award (FMJ) (BX005812); NIH National Institute of Diabetes and Digestive and Kidney Diseases (IIDP) (2UC4DK098085); NIH NIDDK (1K99DK140067)

CD320 Receptor and Vitamin B12 as Potential Targets for Anti-Cancer Therapy

2025-06-12

Ainur Tolymbekova , Larissa Lezina | International Journal of Molecular Sciences

Despite the development of a wide plethora of different anticancer agents, most of them are not used for patient treatment due to adverse effects caused by untargeted cytotoxicity. To prevent … Despite the development of a wide plethora of different anticancer agents, most of them are not used for patient treatment due to adverse effects caused by untargeted cytotoxicity. To prevent this unwanted toxicity, it is necessary to develop therapies discriminating between healthy and cancerous cells. One possible method is to target proteins overexpressed in cancer but not in normal cells. CD320 is a receptor responsible for the uptake of the transcobalamin-bound fraction of vitamin B12 (cobalamin), which is necessary for DNA synthesis, and thus, cell proliferation. CD320 was shown to be overexpressed in many cancers and its potential role as an early cancer biomarker was confirmed in several studies. Consequently, CD320 may represent a promising anti-cancer therapy target. This review summarizes the current advances and perspectives of anti-cancer CD320 targeting therapy, including therapeutic conjugates of vitamin B12, CD320-specific antibodies and nanobodies, nanoparticles loaded with cytotoxic drugs, porphyrin, and the potential of targeted CD320 therapy in attenuation of tumor tissues. Given the growing interest in CD320 as a novel target for anti-cancer therapy, further in vivo studies are required for the investigation of CD320 targeting effects on systemic cytotoxicity.

Atypical acute promyelocytic leukemia with tripartite fusion gene <i>PML::RARG::LINE-L2a</i> is resistant to ATRA but sensitive to arsenic-based therapy

2025-06-12

Sanyun Wu , Yalan Yu , Xiang Lin +7 more | Haematologica

Not available. Not available.

A holistic computational exploration of AZD7762 as a potent selective modulator of LXRα, LXRβ and FXR: An underexplored pathway in cancer therapeutics

2025-06-04

Basanta Singha , Partha Pratim Gogoi , Penlisola Longkumer +4 more | Computers in Biology and Medicine

Arsenic Trioxide Enhances the Efficacy of PD‐1 Inhibitors in Hepatocellular Carcinoma by Inducing Immunogenic Cell Death via the ROS/ERS Pathway

2025-06-01

Xionghui Wang , Simo Cheng , Yannan Xu +3 more | Immunity Inflammation and Disease

ABSTRACT Background Hepatocellular carcinoma (HCC) remains a major global health challenge, with limited efficacy of current immunotherapeutic strategies. Immunogenic cell death (ICD), characterized by the release of damage‐associated molecular patterns … ABSTRACT Background Hepatocellular carcinoma (HCC) remains a major global health challenge, with limited efficacy of current immunotherapeutic strategies. Immunogenic cell death (ICD), characterized by the release of damage‐associated molecular patterns (DAMPs), offers a promising approach to enhance antitumor immunity. Arsenic trioxide (ATO), an ICD inducer, may synergize with PD‐1 inhibitors to overcome therapeutic resistance, though the underlying mechanisms remain unclear. Methods The cytotoxicity of ATO was evaluated via MTT, clonogenic, and apoptosis assays. ROS levels were quantified using ROS fluorescent probes. ERS activation was confirmed by Western blot detection of Calnexin, PDI, ATF‐4, p‐elF2α, and Caspase‐12. ICD induction was assessed by measuring DAMPs (CRT exposure, HMGB1/ATP/IFN‐β release). The roles of ROS/ERS pathways were dissected using NAC (ROS inhibitor) or 4‐PBA (ERS inhibitor) pre‐treatment. Ex vivo dendritic cell maturation assays analyzed ATO‐treated HCC cells' immunostimulatory capacity, while In Vivo models evaluated immune microenvironment modulation via flow cytometry. Prophylactic/therapeutic tumor vaccine experiments assessed antitumor immunity using ATO‐treated HCC cells as vaccines. Synergy between ATO and PD‐1 blockade was tested in tumor‐bearing mice by combining ATO with anti‐PD‐1 antibodies, monitoring tumor growth kinetics and survival outcomes. Results ATO dose‐dependently reduced HCC cell viability while elevating intracellular ROS levels and activating ERS. These processes triggered the release/surface exposure of ICD‐related DAMPs, including CRT, HMGB1, ATP, and IFN‐β, leading to dendritic cells maturation and tumor immune microenvironment remodeling. ATO‐treated HCC cells exhibited enhanced immunogenicity, functioning as prophylactic and therapeutic vaccines to stimulate antitumor immunity. Notably, ATO significantly potentiated the therapeutic efficacy of PD‐1 inhibitors In Vivo. Conclusion ATO induces ICD in HCC via a ROS/ERS signaling axis, thereby amplifying antitumor immune responses and synergizing with PD‐1 blockade. These findings support the clinical evaluation of ATO‐PD‐1 inhibitor combinations to improve outcomes in HCC patients.

Advances of RARα fusion genes in acute promyelocytic leukemia

2025-06-01

Ao Zhang , Shaowei Qiu | Experimental Hematology

ATRA derived lipid nanoparticles for co-delivery of siCYP26A1 to overcome metabolic limitations of differentiation therapy in solid tumors

2025-06-01

Huan Yang , Yiyao Pu , Xueyi Hu +7 more | Journal of Controlled Release

Genotoxic studies of Arsenic trioxide on polychromatic and normochromatic erythrocytes in bone marrow cells of (Mus musculus) swiss albino mice.

2025-06-01

Supriya Bharti , Arvind Kumar | Deleted Journal

The genotoxic potency of Arsenic trioxide in terms of induction of micronucleated polychromatic erythrocytes (MNPCE) and micronucleated Normochromatic erythrocyte (MNNCE) in bone marrow cells in Swiss albino mice (Mus musculus) … The genotoxic potency of Arsenic trioxide in terms of induction of micronucleated polychromatic erythrocytes (MNPCE) and micronucleated Normochromatic erythrocyte (MNNCE) in bone marrow cells in Swiss albino mice (Mus musculus) has been investigated.For the research experiment, Adult Mus musculus of the same age group were selected for the research experiment and divided into three groups (Control, AA-1 & AA-2. After the completion of the treatment, slides wereprepared according to OECD guidelines. For the assessment of frequency of Mn in polychromatic or normochromatic erythrocytes 800 - 900 cells in each treated experimental mice were screened randomly under the compound microscope at 40X. and screening was done by image J microscopy software. Results of the experiment showed that the total frequency of Mn in polychromatic and normochromatic erythrocytes was0.26± 0.77in Control groups, 2.55± 0.23*in AA-1 groups, 5.43± 0.36**in AA-2 groups, it is a significant difference to control and treated group at p < 0.05 or < 0.01. Hence, the results of the research experiment indicate that Arsenic trioxide has the potency to induced genotoxic in Experimental mice (M. musculus).. KEYWORDS :Arsenic, Genotoxic, Bone marrow, Erythrocytes, Mus musculus.

Vitamin A deficiency presenting with ptosis and optic neuropathy in child with autism spectrum disorder

2025-06-01

Ryohei Morita , Kumiko Kato , Ryunosuke Nagashima +3 more | Documenta Ophthalmologica

Improvement Effect of Shengxian Decoction on Cardiac Toxicity Induced by Arsenic Trioxide in Rats

2025-06-01

Yuxia Wang , Jiahao Hou , Yinfeng Yu +6 more | Journal of Ethnopharmacology

RXR agonist S169 inhibits HBV/HDV entry in vitro by disrupting KIF4-dependent NTCP trafficking.

2025-06-01

Sameh A. Gad , Doaa A Abo Elwafa , Salah Eldin Omar Hussein +7 more | Antiviral Research

Comparative evaluation of the biological characteristics of a novel retinoid X receptor agonist and bexarotene

2025-06-01

Koji Tomita , Ken‐ichi Nakashima , Eiji Yamaguchi +3 more | Molecular Pharmacology

Acute Promyelocytic Leukemia Unraveled: Biotechnological Approaches in Targeted Therapies and Molecular Mechanisms - A Review

2025-05-31

Arun R. Nair , Hariharan Venkatesan , R.S. Soumya +1 more | Research Journal of Biotechnology

Acute Promyelocytic Leukemia (APL), a rare subclass of hematological disorder of Acute Myeloid Leukemia, is distinguished due to the existence of promyelocytic leukemia with retinoic acid receptor (PML-RARα) fusion protein. … Acute Promyelocytic Leukemia (APL), a rare subclass of hematological disorder of Acute Myeloid Leukemia, is distinguished due to the existence of promyelocytic leukemia with retinoic acid receptor (PML-RARα) fusion protein. These fusion proteins will disturb and manipulate the normal cell differentiation of leukocytes and will navigate the leukemogenesis. The commencement of target therapies like All-Trans Retinoic acid in combination with arsenic trioxide has drastically altered the treatment prospects regarding APL, handing over extraordinary remissions and better survival outcomes to the medical world. Biotechnological advancement has elucidated the molecular details of the disease which has helped in the creation and development of novel diagnostic tools and therapeutic strategies. Collective actions of ATRA and ATO will disintegrate the PML-RARα fusion protein, will induce apoptosis and will restore normal cell differentiation, thereby bringing out the importance of blending medicines in treatment and targeted therapies in APL management. Over and above, medical biotechnology has unlocked genomic and proteomic assessment and evaluation and uncovered new genetic aberrations and pathways with APL. This study also addresses treatment difficulties like relapse and therapeutic resistance, calling attention to the need for more innovative approaches using biotechnology. Biotechnology has lifted APL therapeutic management to a new high standard for targeted therapies in blood-related cancers by integrating molecular biology with clinical applications.