Resistance to Hypomethylating Agents in Myelodysplastic Syndrome and Acute Myeloid Leukemia From Clinical Data and Molecular Mechanism

Abstract

The nucleoside analogs decitabine (5-AZA-dC) and azacitidine (5-AZA) have been developed as targeted therapies to reverse DNA methylation in different cancer types, and they significantly improve the survival of patients who are not suitable for traditional intensive chemotherapies or other treatment regimens. However, approximately 50% of patients have a response to hypomethylating agents (HMAs), and many patients have no response originally or in the process of treatment. Even though new combination regimens have been tested to overcome the resistance to 5-AZA-dC or 5-AZA, only a small proportion of patients benefited from these strategies, and the outcome was very poor. However, the mechanisms of the resistance remain unknown. Some studies only partially described management after failure and the mechanisms of resistance. Herein, we will review the clinical and molecular signatures of the HMA response, alternative treatment after failure, and the causes of resistance in hematological malignancies.

Enhanced clinical assessment of hematologic malignancies through routine paired tumor:normal sequencing

“…For instance, TP53 mutations are consistently associated with shorter survival after allogeneic stem cell transplantation and somatic mutations in epigenetic pathways (TET2, IDH1/2, WT1, and DNMT3A) may confer increased sensitivity to hypomethylating agents. 14,57,58 Somatic mutations may require reassessment to update individual risk after treatment, at the time of signi cant clinical changes or before disease-modifying treatments. Our approach to testing, incorporating routine sequencing of appropriate control samples, enables the unequivocal identi cation of somatic genetic variants in a way that is scalable even in the context of an allogeneic transplant.…”

“…For instance, while speci c mutations are not required in the FDA approval for hypomethylating agents (HMAs) in myeloid neoplasms, their presence has been associated with response to HMA treatment, and inaccurate reporting could alter choice of therapy. 14 In this analysis we identi ed a total of 83 germline variants from myeloid neoplasms in genes associated with response to HMA treatment that could have been misattributed to being of somatic origin without a matched normal sample: TET2 (n = 47), IDH2 (n = 19), IDH1(n = 10), DNMT3A (n = 4), and TP53 (n = 3) (Supplemental Table 2). In addition, the persistence of somatic alterations is often used to monitor response to therapy, therefore misattribution of these alterations as somatic could lead to inaccurate monitoring results in followup samples.…”

Hypermethylation of the Promoter of miR-338-5p Mediates Aberrant Expression of ETS-1 and Is Correlated With Disease Severity Of Astrocytoma Patients

“…Decitabine is a common and typical DNMT-1 inhibitor, which has a good inhibitory activity on the activity of DNMT-1 (73)(74)(75). While using Decitabine, this study also used inhibitors of other mechanisms.…”

How Azanucleosides Affect Myeloid Cell Fate

“…A number of studies have looked for an influence of mutations in specific genes on the response and outcome of MDS, CMML or AML patients treated with HMAs. Although associations have been reported with mutations in a variety of genes [ 42 , 43 , 44 ], most are weak and there is often inconsistency between studies [ 4 ]. Most importantly, there is no clear influence of DNMT3A mutations on HMA response, while TET2 mutations appear to be relevant only above 10% variable allele frequencies and when considered in conjunction with other markers [ 43 , 45 ].…”