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Mechanistic effects of arsenic trioxide on acute promyelocytic leukemia and other types of leukemias.
Yousefnia, S
Cell biology international. 2021;(6):1148-1157
Abstract
Acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia characterized with a translocation between promyelocytic leukemia gene (PML) on chromosome 15 and retinoic acid receptor alpha gene (RARα) on chromosome 17. Transcription of this fusion gene results in PML/RARα fusion protein blocking expression of critical genes involved in differentiation of myeloid cells through interaction with RAR element. PML/RARα fusion protein prevents normal function of PML and RARα as well as inhibiting apoptosis. Arsenic trioxide (ATO) is an important agent for the treatment of relapsed and newly diagnosed APL. ATO induces apoptosis, autophagy, and partial cellular differentiation as well as inhibiting cell growth and angiogenesis. Recognition of signaling pathways and molecular mechanisms induced by ATO can be effective for discovering novel treatment strategies to target leukemia cells. Also, it can be developed for the treatment of a variety of cancer cells. This review provides a perspective on anticancerous effects of ATO on APL and leukemia cells.
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2.
Chemogenomics analysis of drug targets for the treatment of acute promyelocytic leukemia.
Chen, S, Li, X, Ma, S, Xing, X, Wang, X, Zhu, Z
Annals of hematology. 2020;(4):753-763
Abstract
The main challenges in treating acute promyelocytic leukemia (APL) are currently early mortality, relapse, refractory disease after induction therapy, and drug resistance to ATRA and ATO. In this study, a computational chemogenomics approach was used to identify new molecular targets and drugs for APL treatment. The transcriptional profiles induced by APL were compared with those induced by genetic or chemical perturbations. The genes that can reverse the transcriptional profiles induced by APL when perturbed were considered to be potential therapeutic targets for APL. Drugs targeting these genes or proteins are predicted to be able to treat APL if they can reverse the APL-induced transcriptional profiles. To improve the target identification accuracy of the above correlation method, we plotted the functional protein association networks of the predicted targets by STRING. The results determined PML, RARA, SPI1, HDAC3, CEBPA, NPM1, ABL1, BCR, PTEN, FOS, PDGFRB, FGFR1, NUP98, AFF1, and MEIS1 to be top candidates. Interestingly, the functions of PML, RARA, HDAC3, CEBPA, NPM1, ABL, and BCR in APL have been previously reported in the literature. This is the first chemogenomics analysis predicting potential APL drug targets, and the findings could be used to guide the design of new drugs targeting refractory and recurrent APL.
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3.
Autophagy: New Insights into Mechanisms of Action and Resistance of Treatment in Acute Promyelocytic leukemia.
Moosavi, MA, Djavaheri-Mergny, M
International journal of molecular sciences. 2019;(14)
Abstract
Autophagy is one of the main cellular catabolic pathways controlling a variety of physiological processes, including those involved in self-renewal, differentiation and death. While acute promyelocytic leukemia (APL) cells manifest low levels of expression of autophagy genes associated with reduced autophagy activity, the introduction of all-trans retinoid acid (ATRA)-a differentiating agent currently used in clinical settings-restores autophagy in these cells. ATRA-induced autophagy is involved in granulocytes differentiation through a mechanism that involves among others the degradation of the PML-RARα oncoprotein. Arsenic trioxide (ATO) is another anti-cancer agent that promotes autophagy-dependent clearance of promyelocytic leukemia retinoic acid receptor alpha gene (PML-RARα) in APL cells. Hence, enhancing autophagy may have therapeutic benefits in maturation-resistant APL cells. However, the role of autophagy in response to APL therapy is not so simple, because some autophagy proteins have been shown to play a pro-survival role upon ATRA and ATO treatment, and both agents can activate ETosis, a type of cell death mediated by the release of neutrophil extracellular traps (ETs). This review highlights recent findings on the impact of autophagy on the mechanisms of action of ATRA and ATO in APL cells. We also discuss the potential role of autophagy in the development of resistance to treatment, and of differentiation syndrome in APL.
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4.
Molecular remission as a therapeutic objective in acute promyelocytic leukemia.
Cicconi, L, Fenaux, P, Kantarjian, H, Tallman, M, Sanz, MA, Lo-Coco, F
Leukemia. 2018;(8):1671-1678
Abstract
Acute promyelocytic leukemia (APL) is a subtype of acute leukemia characterized by a unique t(15;17) translocation generating the PML/RARA fusion gene and hybrid oncoprotein. Besides its critical role in leukemogenesis, this genetic aberration serves as a disease-specific biomarker for rapid diagnosis and monitoring of minimal residual disease (MRD). Moreover, PML/RARA is specifically targeted by All-trans retinoic acid (ATRA) and arsenic trioxide (ATO), two agents that synergistically act to induce degradation of the oncoprotein. Large clinical studies including two randomized trials conducted in newly diagnosed APL patients have shown that the ATRA-ATO combination is superior to conventional ATRA and chemotherapy both in terms of efficacy and safety. Preliminary studies using oral formulations of arsenic and ATRA suggest that oral arsenic is as effective and manageable as intravenous ATO. Following early retrospective studies indicating the prognostic relevance of PML/RARA monitoring, several prospective studies were conducted in large cohorts of APL patients enrolled in clinical trials with the aim of better assessing the prognostic value of longitudinal PCR testing. The results consistently showed that molecular remission (defined as negativization of the PCR test for PML/RARA) correlates with a significantly decreased risk of relapse, whereas persistence of PCR positivity for PML/RARA after consolidation or conversion from negative to positive during follow-up is strongly associated with hematologic relapse. Based on these data, various groups started using pre-emptive salvage therapy for patients who persisted PCR-positive after frontline consolidation or converted from negative to positive PCR during follow-up. Finally, several expert panels have recommended that molecular remission should be considered a therapeutic objective in APL, and molecular response has been adopted as a study endpoint in modern clinical trials.
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5.
[Acute Promyelocytic Leukemia: New treatment strategies with ATRA and ATO - AML-BFM-Recommendations].
Creutzig, U, Dworzak, M, von Neuhoff, N, Rasche, M, Reinhardt, D
Klinische Padiatrie. 2018;(6):299-304
Abstract
The treatment of acute promyelocytic leukemia (APL) has changed significantly in recent years. Today, APL patients with standard risk (also known as low risk) can be treated chemotherapy-free only with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO). For high-risk patients, induction chemotherapy should be added. The curative results are good and comparable to those achieved in the past with chemotherapy plus ATRA. However, toxicities, especially infectious complications, are reduced. The main risk remains early lethal bleeding. Timely diagnosis and early ATRA treatment can reduce this risk. This review presents and discusses current treatment strategies and recommendations for APL in children.
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6.
[State-of-the-art treatment of acute promyelocytic leukemia].
Kiguchi, T
[Rinsho ketsueki] The Japanese journal of clinical hematology. 2018;(10):2007-2018
Abstract
Acute promyelocytic leukemia (APL) with PML-RARA is an acute myeloid leukemia (AML) with a predominance of abnormal promyelocytes. Both hypergranular (typical) and microgranular (hypogranular) types exist. Previously, APL was associated with an extremely high mortality rate due to hemorrhage. However, since the advent of anthracycline, all-trans retinoic acid (ATRA) has been introduced into therapy, resulting in the transformation of APL into AML with a higher probability of cure. Furthermore, for the last 30 years, molecular-targeted drugs, such as arsenic acid (ATO), tamibarotene (Am80), and gemtuzumab ozogamicin (GO), have been developed in succession in addition to ATRA. In recent years, molecular-targeted drugs with different mechanisms of action are being combined, and the APL treatment outcome is revolutionary. In this review, we introduce previously used APL therapies and those at the forefront of APL treatment.
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7.
[Acute promyelocytic leukemia: state-of-the-art management].
Asou, N
[Rinsho ketsueki] The Japanese journal of clinical hematology. 2018;(6):725-734
Abstract
Acute promyelocytic leukemia (APL) is driven by the promyelocytic leukemia (PML) -retinoic acid receptor (RAR) α fusion protein generated by the chromosomal translocation t (15;17) which affects both nuclear receptor signaling and PML nuclear body (NB) assembly. The advent of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) as molecular targeted therapies directed against PML-RARα has been a major breakthrough in APL treatment. ATRA and ATO target RARα and PML, respectively, and elicit PML-RARα degradation, leading to the reformation of normal NBs and cell differentiation. In several multicenter trials, more than 90% of newly diagnosed APL patients treated with ATRA and chemotherapy achieved complete remission, of whom 20%-30% subsequently relapsed; the overall survival was approximately 80% in these studies. However, several major clinical problems continue to account for treatment failure including early death due to hemorrhage, infection during consolidation, disease relapse, and secondary malignancies. These issues are associated mainly with anticancer agents used in combination with ATRA. Combination therapy using ATRA and ATO is the current standard therapy for untreated patients with APL in Western countries. The current problems in patients with APL treated with ATRA and ATO are APL differentiation syndrome and high risk of relapse in patients with an initial leukocyte count of more than 10×109/l.
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8.
[The Significance of Genetic Testing for Acute Promyelocytic Leukemia].
Satoh, Y, Masuda, A, Yatomi, Y
Rinsho byori. The Japanese journal of clinical pathology. 2017;(1):37-43
Abstract
The majority of patients with acute promyelocytic leukemia (APL) harbor the t (15;17) (q22;q12) transloca- tion, which results in the expression of PML-RARA mRNA. All-trans retinoic acid (ATRA) is a representa- tive molecular-targeted drug and is directed against PML-RARA. Therefore, the detection of PML-RARA mRNA has become indispensable for the diagnosis of APL and the decision regarding the treatment policy. Once the diagnosis is confirmed by genetic testing, ATRA-based induction therapy can be initiated. This is also applicable in atypical cases such as the M3 variant. Furthermore, after ATRA-based induction therapy, the curative effect is evaluated by quantitative PCR analysis. Thus, genetic testing is important in the follow-up of patients with APL. [Review].
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9.
[Acute promyelocytic leukemia with stat5b- RARα fusiongene: a case report and literatures review].
Liu, L, Chen, S, Tan, J, Shi, P, Chen, K, Gao, D, Huang, X, Xie, Y, Xu, Y, Yang, F, et al
Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi. 2016;(1):68-9
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10.
A case of life-threatening retinoic acid syndrome and review of literature.
Tariq, Z, Phinney, RC, Mohamed, I
American journal of therapeutics. 2014;(2):e28-30
Abstract
All-trans-retinoic acid represents a major progress that has made acute promyelocytic leukemia the most curable subtype of acute myeloid leukemia in adults. Although all-trans-retinoic acid is usually well tolerated, some patients develop the retinoic acid syndrome, characterized by unexplained fever, weight gain, respiratory distress, interstitial pulmonary infiltrates, pleural and pericardial effusions, episodic hypotension, and acute renal failure. Further studies of growth factor expression and modulation of adhesion molecules are warranted to provide further insights into the pathogenesis of the syndrome and may lead to its prevention.