Roles of Histone Deacetylases in Acute Myeloid Leukemia With Fusion Proteins

Zhang, Juan; Gao, Xuefeng; Yu, Li

doi:10.3389/fonc.2021.741746

Cited by 12 publications

(12 citation statements)

References 159 publications

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“…HDACs are proteins involved in the regulation of genetic transcription. 177 In 2022, Hausen's group presented a series of new CRBN‐based PROTACs targeting HDAC6, via a solid‐phase parallel synthesis approach. 178 Among the PROTACs synthesized, PROTAC 81 stands out, which has a DC 50 value of 3.5 nM, and a D max of 80% when tested on AML cell lines.…”

Section: Protacs Against Leukemia‐associated Targetsmentioning

confidence: 99%

PROteolysis‐Targeting Chimeras (PROTACs) in leukemia: overview and future perspectives

Vicente,

Salvador

2024

MedComm

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Leukemia is a heterogeneous group of life‐threatening malignant disorders of the hematopoietic system. Immunotherapy, radiotherapy, stem cell transplantation, targeted therapy, and chemotherapy are among the approved leukemia treatments. Unfortunately, therapeutic resistance, side effects, relapses, and long‐term sequelae occur in a significant proportion of patients and severely compromise the treatment efficacy. The development of novel approaches to improve outcomes is therefore an unmet need. Recently, novel leukemia drug discovery strategies, including targeted protein degradation, have shown potential to advance the field of personalized medicine for leukemia patients. Specifically, PROteolysis‐TArgeting Chimeras (PROTACs) are revolutionary compounds that allow the selective degradation of a protein by the ubiquitin–proteasome system. Developed against a wide range of cancer targets, they show promising potential in overcoming many of the drawbacks associated with conventional therapies. Following the exponential growth of antileukemic PROTACs, this article reviews PROTAC‐mediated degradation of leukemia‐associated targets. Chemical structures, in vitro and in vivo activities, pharmacokinetics, pharmacodynamics, and clinical trials of PROTACs are critically discussed. Furthermore, advantages, challenges, and future perspectives of PROTACs in leukemia are covered, in order to understand the potential that these novel compounds may have as future drugs for leukemia treatment.

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Section: Protacs Against Leukemia‐associated Targetsmentioning

confidence: 99%

PROteolysis‐Targeting Chimeras (PROTACs) in leukemia: overview and future perspectives

Vicente,

Salvador

2024

MedComm

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“…ETO binds to co-inhibitory factors and recruits HDAC1, 2, and three to form co-inhibitory complexes, thus silencing target genes and preventing hematopoietic differentiation and transformation. It also interacts with secondary mutations, including C-KIT, FLT3, and RAS, ultimately leading to the occurrence or progression of AML1-ETO-positive leukemia (Zhang et al, 2021). The chidamide-based 3-drug combination regimen adopted in this study is based on the theory of correcting epigenetic disorders.…”

Section: Figurementioning

confidence: 99%

Chidamide-based 3-drug combination regimen reverses molecular relapse post transplantation in AML1-ETO–positive acute myeloid leukemia

Yang

Li²,

Zhang³

et al. 2023

Front. Pharmacol.

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Objective: We aimed to explore a new method to reverse early relapse in patients with AML1-ETO–positive acute myeloid cell transplantation.Methods: A chidamide-based 3-drug combination regimen was used in our center to treat patients with AML1-ETO–positive AML post transplantation but negative flow cytometry results. A retrospective analysis was performed of the survival rate and possible influencing factors of patients with relapse treated with this regimen in our center from January 2018 to January 2022.Results: The overall response rate was 95.8% (23/24), and the median number of treatment courses was 4 (range, 3–12 courses). The total molecular complete response (MCR) was 79.1% (19/24) after all treatments, and the molecular complete response was 37.5% (9/24) after one cycle of treatment but reached 58.3% (14/24) after four cycles; overall, the proportion of MCR increased gradually with the increase in treatment cycles. The projected 5-year overall survival rate was 73.9%. The projected 5-year leukemia-free survival rate was 64.8%, and the projected 1-year cumulative relapse rate was 35.5%. The incidence of grade II–IV graft-versus-host diseases (GVHD) was 29.2% (7/24), and that of grade III–IV GVHD was 20.8% (5/24), which could be effectively controlled by glucocorticoid therapy combined with calcineurin inhibitors The total incidence of chronic GVHD was 29.2% (7/24), and all cases were localized chronic GVHD. The total infection rate was 33.3% (8/24), mainly involving bacterial and fungal infections, and the incidence of life-threatening infections was 4.17% (1/24). The treatment-related mortality rate was 0%; and the total mortality rate was 20.8% (5/24). Nausea and vomiting, thrombocytopenia, and neutropenia were common adverse reactions, all of which were Common Terminology Criteria for Adverse Events grade 2–3 events and reversible after drug withdrawal. In terms of immunity, Th1 cell counts gradually increased, Th17 cell counts gradually decreased, and the Th1/Th17 ratio gradually increased after treatment. The CD8+ T lymphocyte count increased gradually, while the CD4+ T lymphocyte count did not change significantly.Conclusion: Our chidamide-based 3-drug combination regimen led to a high remission rate and tolerable adverse reactions in patients with AML1-ETO–positive post-transplant relapse, and most patients can achieve long-term survival with this regimen.

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“…Topic 4 is strongly associated w ith NPM1 and IDH1/IDH2 mutations and interestingly include a DMR close to CD34, the definitive marker for hematopoietic stem/progenitor cells. Other AML associated genes selected in Topic 4 include HDAC4, a key epigenetic regulator in AML 74,75 . Topic 13, enriched for NPM1 and WT1 mutations, also has DMRs near HOXB3.…”

Section: Acknowledgementmentioning

confidence: 99%

Computational modeling of methylation impact of AML drivers reveals new pathways and refines AML risk-stratification

Gurun

Tyner

Demir

et al. 2023

Preprint

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Decades before its clinical onset, epigenetic changes start to accumulate in the progenitor cells of Acute Myelogenous Leukemia (AML). Delineating these changes can improve risk-stratification for patients and shed insights into AML etiology, dynamics and mechanisms. Towards this goal, we extracted epigenetic signatures through two parallel machine learning approaches: a supervised regression model using frequently mutated genes as labels and an unsupervised topic modeling approach to factorize covarying epigenetic changes into a small number of topics. First, we created regression models for DNMT3A and TET2, the two most frequently mutated epigenetic drivers in AML. Our model differentiated wild-type vs. mutant genotypes based on their downstream epigenetic impacts with very high accuracy: AUROC 0.9 and 0.8, respectively. Methylation loci frequently selected by the models recapitulated known downstream pathways and identified several novel recurrent targets. Second, we used topic modeling to systematically factorize the high dimensional methylation profiles to a latent space of 15 topics. We annotated identified topics with biological and clinical features such as mutation status, prior malignancy and ELN criteria. Topic modeling successfully deconvoluted the combined effects of multiple upstream epigenetic drivers into individual topics including relatively infrequent cytogenetic events, improving the methylation-based subtyping of AML. Furthermore, they revealed complimentary and synergistic interactions between drivers, grouped them based on the similarity of their downstream methylation impact and linked them to prognostic criteria. Our models identify new signatures and methylation pathways, refine risk-stratification and inform detection and drug response studies for AML patients.

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Roles of Histone Deacetylases in Acute Myeloid Leukemia With Fusion Proteins

Cited by 12 publications

References 159 publications

PROteolysis‐Targeting Chimeras (PROTACs) in leukemia: overview and future perspectives

PROteolysis‐Targeting Chimeras (PROTACs) in leukemia: overview and future perspectives

Chidamide-based 3-drug combination regimen reverses molecular relapse post transplantation in AML1-ETO–positive acute myeloid leukemia

Computational modeling of methylation impact of AML drivers reveals new pathways and refines AML risk-stratification

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