Available online 20 October 2023, 101521

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Myeloid malignancies such as myelodysplastic syndrome (MDS) & acute myeloid leukemia (AML) are clonal diseases that emerge and progress due to the expansion of disease-initiating aberrant hematopoietic stem cells, that are not eliminated by conventional cytotoxic therapies. Hypomethylating agents(HMA), azacytidine and decitabine are the first line agents for treatment of MDS and a combination with BCL-2 inhibitor, venetoclax, is approved for AML induction in patients above 75 years and is also actively being investigated for use in high risk MDS. Resistance to these drugs has become a significant clinical challenge in treatment of myeloid malignancies. In this review, we discuss molecular mechanisms underlying the development of resistance to HMA and venetoclax. Insights into these mechanisms can help identify potential biomarkers for resistance prediction, aid in the development of combination therapies and strategies to prevent resistance and advance the field of cancer therapeutics.

Section snippetsIntroduction:

Myeloid malignancies such as myelodysplastic syndrome (MDS) & acute myeloid leukemia (AML) are clonal diseases that emerge and progress due to the expansion of disease-initiating aberrant hematopoietic stem cells, that are not eliminated by conventional cytotoxic therapies. The past 10 years have seen significant therapeutic advances for the treatment of myeloid malignancies with the FDA approvals of several potent classes of drugs for Acute myeloid leukemia (AML)(1). The combination of the

HENT1 transporter expression

The first step in mechanism of action of azanucleoside analogues is transport of the chemotherapeutic drug across the plasma membrane of MDS and AML cells(9). Human concentrative nucleoside transporter (hCNT) and human equilibriative nucleoside transporter (hENT) family of proteins that are expressed selectively in epithelial cells and ubiquitously respectively are responsible for uptake of nucleosides and their naturally occurring analogues(9). In-vitro studies on human leukemic cell lines and

DNMT1

DNA methyltransferase 1 is an enzyme encoded by DNMT1 gene that catalyzes DNA methylation, a process where in methyl groups are transferred to specific CpG islands of DNA(26). DNA methylation is an important step in epigenetic regulation(27). The deoxycytidine triphosphate analogues of 5-azacytidine and decitabine cause DNMT1 depletion thereby terminating self-replication of malignant cells(28, 29). DNMT1 protein quantification was performed on serial bone marrow samples, pre and post treatment

Overexpression of antiapoptotic BCL-2 family members

Solid tumors such as breast cancer utilize hyperexpression of anti-apoptotic BCL-2 family members to evade programmed cell death (48). Such phenomenon is also observed in malignant cell lines treated with BCL-2 inhibitors contributing to their resistance. ABT-737 is an orally bioavailable BH3 mimetic that inhibits multiple anti-apoptotic BCL-2 family members: BCL-2, BCL-xl and BCL-w (49). Elevated induced myeloid leukemia cell differentiation 1 (MCL-1) correlated with resistance to ABT-737 in

Conclusion:

Mechanisms of resistance to HMA’s and Venetoclax are complex, multifactorial and adaptive as clearly explained in this review. While we have detailed several known mechanisms of resistance here, there are several that are yet to be uncovered and could play an important role in therapy resistance. A very clear emerging theme however is that a single strategy or drug to overcome therapy resistance will never be adequate and after initial dose finding studies of novel agents, effective

Declaration of Competing Interest

Aditi Shastri, MBBS, has the following relevant financial relationships: Grant/Research Support: Kymera Therapeutics Consultant/Advisory Board: Gilead Sciences, Rigel Pharmaceuticals, Kymera Therapeutics, Janssen Pharmaceuticals

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© 2023 Published by Elsevier Ltd.