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PARP inhibitors (PARPi) represent a novel class of targeted therapies that have conventionally been used for the treatment of BRCA1/2-mutated solid tumors. PARP1 being an indispensable component of the DNA repair machinery is essential for maintaining genomic integrity. Germline mutations or expression changes in genes compromising homologous recombination (HR)-mediated repair increases dependency on PARP1 and sensitizes these cells to PARP inhibition. Unlike solid tumors, hematologic malignancies do not frequently harbor BRCA1/2 mutations. PARP inhibition as a therapeutic strategy in blood disorders, therefore, did not receive the same importance. However, underlying epigenetic plasticity and leveraging transcriptional dependencies across molecular subtypes of leukemia has invigorated PARP inhibition-guided synthetic lethality in hematologic malignancies. For example, recent studies showing the importance of robust DNA repair machinery in acute myeloid leukemia (AML) increased the evidence of genomic instability associated with leukemia-driven mutations, and compromised repair pathways in certain subgroups of AML has shifted the focus on exploiting PARPi synthetic lethality in leukemia. Single-agent PARPi as well as combination with other targeted therapies has shown promising results in clinical trials involving patients with AML and myelodysplasia. In this study, we evaluated antileukemic potential of PARPi, understood the subtype-dependent differential responses, discussed recent clinical trials, and provided an outlook for future combination therapy strategies. Extensive genetic and epigenetic characterization, utilizing results from completed and ongoing studies will further help to determine specific subset of patients who may respond, and to establish PARPi as a mainstay in leukemia treatment., Competing Interests: Conflict of Interest Disclosure The authors do not have any conflicts of interest to declare in relation to this work., (Copyright © 2023 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

Acute myeloid leukemia (AML) is an aggressive, disseminated hematological malignancy associated with clonal selection of aberrant self-renewing hematopoietic stem cells and progenitors and poorly differentiated myeloid blasts. The most prevalent form of leukemia in adults, AML is predominantly an age-related disorder and accounts for more than 10,000 deaths per year in the United States alone. In comparison to solid tumors, AML has an overall low mutational burden, albeit more than 70% of AML patients harbor somatic mutations in genes encoding epigenetic modifiers and chromatin regulators. In the past decade, discoveries highlighting the role of DNA and histone modifications in determining cellular plasticity and lineage commitment have attested to the importance of epigenetic contributions to tumor cell de-differentiation and heterogeneity, tumor initiation, maintenance, and relapse. Orchestration in histone methylation levels regulates pluripotency and multicellular development. The increasing number of reversible methylation regulators being identified, including histone methylation writer, reader, and eraser enzymes, and their implications in AML pathogenesis have widened the scope of epigenetic reprogramming, with multiple drugs currently in various stages of preclinical and clinical trials. AML methylome also determines response to conventional chemotherapy, as well as AML cell interaction within a tumor-immune microenvironment ecosystem. Here we summarize the latest developments focusing on molecular derangements in histone methyltransferases (HMTs) and histone demethylases (HDMs) in AML pathogenesis. AML-associated HMTs and HDMs, through intricate crosstalk mechanisms, maintain an altered histone methylation code conducive to disease progression. We further discuss their importance in governing response to therapy, which can be used as a biomarker for treatment efficacy. Finally we deliberate on the therapeutic potential of targeting aberrant histone methylome in AML, examine available small molecule inhibitors in combination with immunomodulating therapeutic approaches and caveats, and discuss how future studies can enable posited epigenome-based targeted therapy to become a mainstay for AML treatment., Competing Interests: Conflict of interest disclosure The authors declare no conflicts of interest., (Copyright © 2020 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

Acute myeloid leukemia (AML) remains an aggressive hematopoietic malignancy that is caused by proliferation of immature myeloid cells and is frequently characterized by perturbations in chromatin-modifying enzymes. Emerging evidence indicates that histone demethylases play a role in tumorigenesis. However, due to the complexity of this enormous family of histone-modifying enzymes, substrate redundancy, and context-specific roles, the contribution of each member remains ambiguous and targeting them remains challenging. Here, we analyzed expression of histone-3-lysine (H3K) demethylases and their cognate substrates in a cohort of de novo AML patients, which demonstrated that the expression of H3K27Me3/2-demethylases and selected members of H3K9Me3/2/1-demethylases are significantly increased in AML. KDM6 upregulation is associated with a global decrease in H3K27Me3 level. Importantly, our data show that pharmacological inhibition of H3K27Me3/2-demethylases or H3K9Me3/2-demethylases, either alone or in combination, could be considered an interesting molecular therapeutic modality in human AML independent of its subtype., (Copyright © 2018 ISEH – Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)