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1.
Acute promyelocytic leukemia with myelofibrosis: A case report and literature review.
Xiao, M, Qin, L, Niu, X, Zhou, P, Niu, J, Wei, S, Li, D, Dou, L, Zhang, W, Zhang, L, et al
Medicine. 2021;(13):e24567
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Abstract
RATIONALE Acute promyelocytic leukemia (APL) with myelofibrosis (MF) is rare, and only 14 cases have been reported in the literature to date. PATIENT CONCERNS A 42-year-old woman was admitted to the hospital with easy bruising and excessive bleeding. With the remission of the primary disease during treatment, the degree of fibrosis did not decrease, but worsened progressively. DIAGNOSIS The woman was diagnosed with acute promyelocytic leukemia with secondary myelofibrosis. INTERVENTIONS All-trans retinoic acid (ATRA) was discontinued after 6 months of complete remission of APL. Arsenic trioxide (ATO) was discontinued because of supraventricular tachycardia 9 months after complete remission of APL. OUTCOMES After withdrawal of ATRA for 2 months, the degree of fibrosis was significantly alleviated, and after withdrawal of ATRA for 8 months and ATO for 5 months, bone marrow biopsy showed no reticular fiber deposition. LESSONS In this case report and review of an additional 14 cases of APL with MF, we highlighted the importance of the degree of MF to be evaluated by bone marrow biopsy at the time of bone marrow aspiration when APL is suspected. If MF is present, the type of MF should be determined in a timely manner, and appropriate intervention measures should be taken accordingly.
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Acute Promyelocytic Leukemia and HIV: Case Reports and a Review of the Literature.
Kunitomi, A, Hasegawa, Y, Lmamura, J, Yokomaku, Y, Tokunaga, T, Miyata, Y, Iida, H, Nagai, H
Internal medicine (Tokyo, Japan). 2019;(16):2387-2391
Abstract
Acute promyelocytic leukemia (APL) in human immunodeficiency virus (HIV)-infected individuals is very rare. There is currently no consensus regarding the use of anti-cancer drugs with highly active anti-retroviral therapy (ART) in these patients due to their small number. We herein report two cases of APL with HIV-infected patients. Both cases received all-trans-retinoic acid-containing chemotherapies and achieved complete remission. ART was continued throughout the treatment course. The clinical course of these cases suggests that it is preferable to perform standard chemotherapy for APL with ART if patients have an adequate performance status.
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[Research advances in the protective effect of all-trans retinoic acid against podocyte injury].
Chen, XP, Qin, YH
Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics. 2017;(6):719-723
Abstract
All-trans retinoic acid (ATRA) is a vitamin A derivative and plays an important role in the regulation of cell aggregation, differentiation, apoptosis, proliferation, and inflammatory response. In recent years, some progress has been made in the role of ATRA in renal diseases, especially its protective effect on podocytes. This article reviews the research advances in podocyte injury, characteristics of ATRA, podocyte differentiation and regeneration induced by ATRA, and the protective effect of ATRA against proliferation, deposition of fibers, and apoptosis.
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4.
Reprogramming acute myeloid leukemia into sensitivity for retinoic-acid-driven differentiation.
van Gils, N, Verhagen, HJMP, Smit, L
Experimental hematology. 2017;:12-23
Abstract
The success of all-trans retinoic acid (ATRA) therapy for acute promyelocytic leukemia (APL) provides a rationale for using retinoic acid (RA)-based therapy for other subtypes of acute myeloid leukemia (AML). Recently, several studies showed that ATRA may drive leukemic cells efficiently into differentiation and/or apoptosis in a subset of AML patients with an NPM1 mutation, a FLT3-ITD, an IDH1 mutation, and patients overexpressing EVI-1. Because not all patients within these molecular subgroups respond to ATRA and clinical trials that tested ATRA response in non-APL AML patients have had disappointing results, the identification of additional biomarkers may help to identify patients who strongly respond to ATRA-based therapy. Searching for response biomarkers might also reveal novel RA-based combination therapies with an efficient differentiation/apoptosis-inducing effect in non-APL AML patients. Preliminary studies suggest that the epigenetic or transcriptional state of leukemia cells determines their susceptibility to ATRA. We hypothesize that reprogramming by inhibitors of epigenetic-modifying enzymes or by modulation of microRNA expression might sensitize non-APL AML cells for RA-based therapy. AML relapse is caused by a subpopulation of leukemia cells, named leukemic stem cells (LSCs), which are in a different epigenetic state than the total bulk of the AML. The survival of LSCs after therapy is the main cause of the poor prognosis of AML patients, and novel differentiation therapies should drive these LSCs into maturity. In this review, we summarize the current knowledge on the epigenetic aspects of susceptibility to RA-induced differentiation in APL and non-APL AML.
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5.
Retinoic acid, CYP26, and drug resistance in the stem cell niche.
Alonso, S, Jones, RJ, Ghiaur, G
Experimental hematology. 2017;:17-25
Abstract
The bone marrow niche is essential for hematopoietic stem cells to maintain lifelong blood production by balancing their self-renewal and differentiation. Hematologic malignancies have a similar hierarchical organization to their normal counterparts, with rare populations of cancer stem cells that rely on the microenvironment to survive and propagate their differentiated malignant progenitor cells. Cancer cells alter their microenvironment to create a supportive niche, where they endure chemotherapy, survive as minimal residual disease (MRD), and eventually prevail at relapse. Powerful morphogens, such as retinoids, Wnt/βcatenin, Notch, and Hedgehog, control stem cell fates across tissues, including normal and malignant hematopoiesis. The molecular conversations between these pathways and the mechanisms that control their activity and create gradients at cellular scale remain a mystery. Here, we discuss accumulating evidence suggesting that cytochrome P450 (CYP26), the primary retinoid-inactivating enzyme, plays a critical role in the integration of two of these molecular programs: the retinoid and Hedgehog pathways. Induction of stromal CYP26 by either one of these pathways limits retinoic acid concentration in the stem cell niche, with profound effects on tissue homeostasis and drug resistance. Bypassing this gatekeeping mechanism holds promise for overcoming drug resistance and improving clinical outcomes in hematological malignancies and cancer in general.
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6.
Accelerated Skeletal Maturation in Disorders of Retinoic Acid Metabolism: A Case Report and Focused Review of the Literature.
Nilsson, O, Isoherranen, N, Guo, MH, Lui, JC, Jee, YH, Guttmann-Bauman, I, Acerini, C, Lee, W, Allikmets, R, Yanovski, JA, et al
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2016;(11):737-744
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Abstract
Nutritional excess of vitamin A, a precursor for retinoic acid (RA), causes premature epiphyseal fusion, craniosynostosis, and light-dependent retinopathy. Similarly, homozygous loss-of-function mutations in CYP26B1, one of the major RA-metabolizing enzymes, cause advanced bone age, premature epiphyseal fusion, and craniosynostosis. In this paper, a patient with markedly accelerated skeletal and dental development, retinal scarring, and autism-spectrum disease is presented and the role of retinoic acid in longitudinal bone growth and skeletal maturation is reviewed. Genetic studies were carried out using SNP array and exome sequencing. RA isomers were measured in the patient, family members, and in 18 age-matched healthy children using high-performance liquid chromatography coupled to tandem mass spectrometry. A genomic SNP array identified a novel 8.3 megabase microdeletion on chromosome 10q23.2-23.33. The 79 deleted genes included CYP26A1 and C1, both major RA-metabolizing enzymes. Exome sequencing did not detect any variants that were predicted to be deleterious in the remaining alleles of these genes or other known retinoic acid-metabolizing enzymes. The patient exhibited elevated plasma total RA (16.5 vs. 12.6±1.5 nM, mean±SD, subject vs. controls) and 13-cisRA (10.7 nM vs. 6.1±1.1). The findings support the hypothesis that elevated RA concentrations accelerate bone and dental maturation in humans. CYP26A1 and C1 haploinsufficiency may contribute to the elevated retinoic acid concentrations and clinical findings of the patient, although this phenotype has not been reported in other patients with similar deletions, suggesting that other unknown genetic or environmental factors may also contribute.
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Synergistic targeted therapy for acute promyelocytic leukaemia: a model of translational research in human cancer.
Mi, JQ, Chen, SJ, Zhou, GB, Yan, XJ, Chen, Z
Journal of internal medicine. 2015;(6):627-42
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Abstract
Acute promyelocytic leukaemia (APL), the M3 subtype of acute myeloid leukaemia, was once a lethal disease, yet nowadays the majority of patients with APL can be successfully cured by molecularly targeted therapy. This dramatic improvement in the survival rate is an example of the advantage of modern medicine. APL is characterized by a balanced reciprocal chromosomal translocation fusing the promyelocytic leukaemia (PML) gene on chromosome 15 with the retinoic acid receptor α (RARα) gene on chromosome 17. It has been found that all-trans-retinoic acid (ATRA) or arsenic trioxide (ATO) alone exerts therapeutic effect on APL patients with the PML-RARα fusion gene, and the combination of both drugs can act synergistically to further enhance the cure rate of the patients. Here, we provide an insight into the pathogenesis of APL and the mechanisms underlying the respective roles of ATRA and ATO. In addition, treatments that lead to more effective differentiation and apoptosis of APL cells, including leukaemia-initiating cells, and more thorough eradication of the disease will be discussed. Moreover, as a model of translational research, the development of a cure for APL has followed a bidirectional approach of 'bench to bedside' and 'bedside to bench', which can serve as a valuable example for the diagnosis and treatment of other malignancies.
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Role of cell cycle regulatory molecules in retinoic acid- and vitamin D3-induced differentiation of acute myeloid leukaemia cells.
Hu, XT, Zuckerman, KS
Cell proliferation. 2014;(3):200-10
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Abstract
The important role of cell cycle regulatory molecules in all trans-retinoic acid (ATRA)- and vitamin D3-induced growth inhibition and differentiation induction has been intensively studied in both acute myeloid leukaemia primary cells and a variety of leukaemia cell lines. Cyclin-dependent kinases (CDK)-activating kinase has been demonstrated to interact with retinoic acid receptor (RAR)α in acute promyelocytic leukaemia cells, and inhibition of CDK-activating kinase by ATRA causes hypophosphorylation of PML-RARα, leading to myeloid differentiation. In many cases, downregulation of CDK activity by ATRA and vitamin D3 is a result of elevated p21- and p27-bound CDKs. Activation of p21 is regulated at the transcriptional level, whereas elevated p27 results from both (indirectly) transcriptional activation and post-translational modifications. CDK inhibitors (CKIs) of the INK family, such as p15, p16 and p18, are mainly involved in inhibition of cell proliferation, whereas CIP/KIP members, such as p21, regulate both growth arrest and induction of differentiation. ATRA and vitamin D3 can also downregulate expression of G1 CDKs, especially CDK2 and CDK6. Inhibition of cyclin E expression has only been observed in ATRA- but not in vitamin D3-treated leukaemic cells. In vitro, not only dephosphorylation of pRb but also elevation of total pRb is required for ATRA and vitamin D3 to suppress growth and trigger their differentiation. Finally, sharp reduction in c-Myc has been observed in several leukaemia cell lines treated with ATRA, which may regulate expression of CDKs and CKIs.
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Contemporary treatment of APL.
Cull, EH, Altman, JK
Current hematologic malignancy reports. 2014;(2):193-201
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Abstract
Acute promyelocytic leukemia (APL) is characterized by coagulopathy, leukopenic presentation and sensitivity to anthracyclines, all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). For the last 25 years, APL has been treated with a combination of ATRA and chemotherapy for induction followed by consolidation and maintenance therapy. This general treatment approach has resulted in cure rates of 80-90 %. ATO, originally approved in relapsed APL, has been incorporated into contemporary upfront treatment regimens with excellent response rates. Recent studies show that most patients with APL can be cured with ATRA and ATO alone, eliminating cytotoxic chemotherapy and resulting in superior outcomes compared to standard treatment. We will herein review historical treatment of APL, treatment considerations in specific patient populations, and therapeutic updates.
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The roles of retinoic acid and retinoic acid receptors in inducing epigenetic changes.
Urvalek, A, Laursen, KB, Gudas, LJ
Sub-cellular biochemistry. 2014;:129-49
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Abstract
Epigenetics is "the branch of biology which studies the causal interactions between genes and their products which bring the phenotype into being" as defined by Conrad Waddington in 1942 in a discussion of the mechanisms of cell differentiation. More than seven decades later we know that these mechanisms include histone tail post-translational modifications, DNA methylation, ATP-dependent chromatin remodeling, and non-coding RNA pathways. Epigenetic modifications are powerful drugs targets, and combined targeting of multiple pathways is expected to significantly advance cancer therapy.