DNMT3A mutations promote anthracycline resistance in acute myeloid leukemia via impaired nucleosome remodeling

Abstract

Although the majority of acute myeloid leukemia (AML) patients initially respond to chemotherapy, many patients subsequently relapse; the mechanistic basis for AML persistence following chemotherapy has not been delineated. Recurrent somatic mutations in DNA methyltransferase 3A (DNMT3A), most frequently at arginine 882 (DNMT3Amut), are observed in AML1–3 and in individuals with clonal hematopoiesis in the absence of leukemic transformation4,5. DNMT3Amut AML patients have an inferior outcome when treated with standard-dose daunorubicin-based induction chemotherapy6,7, suggesting that DNMT3Amut cells persist and drive relapse8. Here we show that Dnmt3amut induces hematopoietic stem cell (HSC) expansion, cooperates with Flt3ITD and Npm1c to induce AML in vivo, and promotes resistance to anthracycline chemotherapy. In AML patients, DNMT3AR882 mutations predict for minimal residual disease (MRD), underscoring their role in AML chemoresistance. DNMT3Amut cells show impaired nucleosome eviction and chromatin remodeling in response to anthracyclines, resulting from attenuated recruitment of histone chaperone SPT-16 following anthracycline exposure. This defect leads to an inability to sense and repair DNA torsional stress, which results in increased mutagenesis. Our studies identify a critical role for DNMT3AR882 mutations in driving AML chemoresistance, and highlight the importance of chromatin remodeling in response to cytotoxic chemotherapy.

Conditional knockin of Dnmt3a R878H initiates acute myeloid leukemia with mTOR pathway involvement

“…These data indicated that Dnmt3a mutation could promote proliferation of leukemic stem/progenitor cells by accelerating the transition of HSPCs from a quiescent status to an active one. However, it was just reported that a knockin of the same allele did not cause leukemia on its own with a 2-y follow-up (24). The generation of distinct phenotypes might be caused by different conditional knockin design, mice strain, and so forth.…”

Haploinsufficiency for DNA methyltransferase 3A predisposes hematopoietic cells to myeloid malignancies

“…The alterations in DNA methylation are subtle and are not associated with reproducible changes in gene expression patterns in either humans or mice, even with comprehensive RNA-seq approaches in human AML samples (15) and single cell RNA-seq (this study). Alternative mechanisms have also been shown to exist (such as an altered sensitivity of Dnmt3a mutant cells to chemotherapeutic drugs) (43). However, the downstream consequences of loss-of-function mutations in DNMT3A and the mechanisms by which they act to initiate AML are unclear at this time.…”

Epigenetic dysregulation of hematopoietic stem cells and preleukemic state

“…-mutated AML cells show chemoresistance to anthracyclines by impaired nucleosome eviction and chromatic remodeling in response to anthracyclines, which resulted from attenuated recruitment of histone chaperone SPT-16, leading to defective DNA damage response [34]. This result, at least partially, explains why DNMT3A…”