The curious case of IDH mutant acute myeloid leukaemia: biochemistry and therapeutic approaches

Gruber, Emily; Kats, Lev

doi:10.1042/bst20230017

Cited by 3 publications

(2 citation statements)

References 119 publications

(192 reference statements)

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“…The emergence of resistance to these agents, however, represents an ongoing clinical challenge. The development, clinical application and resistance mechanisms for FLT3 and IDH inhibitors have been extensively reviewed previously [ 32 , 33 ]. Here, we describe the development and clinical use in AML of the Bcl-2 antagonist, venetoclax, and focus on the current knowledge of intrinsic and acquired mechanisms of venetoclax resistance in AML, and emerging approaches to combat this.…”

Section: Existing Therapies For Amlmentioning

confidence: 99%

Venetoclax therapy and emerging resistance mechanisms in acute myeloid leukaemia

Nwosu,

Ross,

Powell

et al. 2024

Cell Death Dis

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Acute myeloid leukaemia (AML) is a highly aggressive and devastating malignancy of the bone marrow and blood. For decades, intensive chemotherapy has been the frontline treatment for AML but has yielded only poor patient outcomes as exemplified by a 5-year survival rate of < 30%, even in younger adults. As knowledge of the molecular underpinnings of AML has advanced, so too has the development new strategies with potential to improve the treatment of AML patients. To date the most promising of these targeted agents is the BH3-mimetic venetoclax which in combination with standard of care therapies, has manageable non-haematological toxicity and exhibits impressive efficacy. However, approximately 30% of AML patients fail to respond to venetoclax-based regimens and almost all treatment responders eventually relapse. Here, we review the emerging mechanisms of intrinsic and acquired venetoclax resistance in AML and highlight recent efforts to identify novel strategies to overcome resistance to venetoclax.

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Section: Existing Therapies For Amlmentioning

confidence: 99%

Venetoclax therapy and emerging resistance mechanisms in acute myeloid leukaemia

Nwosu,

Ross,

Powell

et al. 2024

Cell Death Dis

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“…The conversion of isocitrate to a-KG by IDH1/2 generates a crucial reducing agent, NADPH, which plays a pivotal role in regulating cellular defense mechanisms against oxidative stress through reduction of glutamine metabolism [ 159 ]. During this process, cells produce citrate and acetyl-CoA to sustain lipid metabolism and promote cellular growth under hypoxic conditions [ 160 ]. a-KG also binds to JmjC domain-containing histone demethylases (JmjC KDMs), TET2 and EGLN family of prolyl hydroxylases (PHDs), and ALKB homolog (ALKBH) DNA repair enzymes which have crucial roles in histone methylation, DNA methylation, and DNA repair, respectively [ 161 , 162 ].…”

Section: Dna Methylome Modifiers and Their Roles In Flt3-itd Amlmentioning

confidence: 99%

Emerging DNA Methylome Targets in FLT3-ITD-Positive Acute Myeloid Leukemia: Combination Therapy with Clinically Approved FLT3 Inhibitors

Tecik,

Adan

2024

Curr. Treat. Options in Oncol.

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Opinion statementThe internal tandem duplication (ITD) mutation of the FMS-like receptor tyrosine kinase 3 (FLT3-ITD) is the most common mutation observed in approximately 30% of acute myeloid leukemia (AML) patients. It represents poor prognosis due to continuous activation of downstream growth-promoting signaling pathways such as STAT5 and PI3K/AKT. Hence, FLT3 is considered an attractive druggable target; selective small FLT3 inhibitors (FLT3Is), such as midostaurin and quizartinib, have been clinically approved. However, patients possess generally poor remission rates and acquired resistance when FLT3I used alone. Various factors in patients could cause these adverse effects including altered epigenetic regulation, causing mainly abnormal gene expression patterns. Epigenetic modifications are required for hematopoietic stem cell (HSC) self-renewal and differentiation; however, critical driver mutations have been identified in genes controlling DNA methylation (such as DNMT3A, TET2, IDH1/2). These regulators cause leukemia pathogenesis and affect disease diagnosis and prognosis when they co-occur with FLT3-ITD mutation. Therefore, understanding the role of different epigenetic alterations in FLT3-ITD AML pathogenesis and how they modulate FLT3I’s activity is important to rationalize combinational treatment approaches including FLT3Is and modulators of methylation regulators or pathways. Data from ongoing pre-clinical and clinical studies will further precisely define the potential use of epigenetic therapy together with FLT3Is especially after characterized patients’ mutational status in terms of FLT3 and DNA methlome regulators.

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Clinical Implications of Isocitrate Dehydrogenase Mutations and Targeted Treatment of Acute Myeloid Leukemia with Mutant Isocitrate Dehydrogenase Inhibitors—Recent Advances, Challenges and Future Prospects

Kowalczyk,

Zarychta,

Lejman

et al. 2024

IJMS

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Despite the better understanding of the molecular mechanisms contributing to the pathogenesis of acute myeloid leukemia (AML) and improved patient survival in recent years, AML therapy still remains a clinical challenge. For this reason, it is important to search for new therapies that will enable the achievement of remission. Recently, the Food and Drug Administration approved three mutant IDH (mIDH) inhibitors for the treatment of AML. However, the use of mIDH inhibitors in monotherapy usually leads to the development of resistance and the subsequent recurrence of the cancer, despite the initial effectiveness of the therapy. A complete understanding of the mechanisms by which IDH mutations influence the development of leukemia, as well as the processes that enable resistance to mIDH inhibitors, may significantly improve the efficacy of this therapy through the use of an appropriate synergistic approach. The aim of this literature review is to present the role of IDH1/IDH2 mutations in the pathogenesis of AML and the results of clinical trials using mIDH1/IDH2 inhibitors in AML and to discuss the challenges related to the use of mIDH1/IDH2 inhibitors in practice and future prospects related to the potential methods of overcoming resistance to these agents.

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The curious case of IDH mutant acute myeloid leukaemia: biochemistry and therapeutic approaches

Cited by 3 publications

References 119 publications

Venetoclax therapy and emerging resistance mechanisms in acute myeloid leukaemia

Venetoclax therapy and emerging resistance mechanisms in acute myeloid leukaemia

Emerging DNA Methylome Targets in FLT3-ITD-Positive Acute Myeloid Leukemia: Combination Therapy with Clinically Approved FLT3 Inhibitors

Clinical Implications of Isocitrate Dehydrogenase Mutations and Targeted Treatment of Acute Myeloid Leukemia with Mutant Isocitrate Dehydrogenase Inhibitors—Recent Advances, Challenges and Future Prospects

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