Dnmt3a regulates T-cell development and suppresses T-ALL transformation

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic neoplasm resulting from the malignant transformation of T-cell progenitors, and comprises approximately 15% and 25% of pediatric and adult ALL cases respectively. It is well-established that activating NOTCH1 mutations are the major genetic lesions driving T-ALL in most patients, but efforts to develop targeted therapies against this pathway have produced limited success in decreasing leukemic burden and come with significant clinical side effects. A finer detailed understanding of the genetic and molecular mechanisms underlying T-ALL is required identify patients at increased risk for treatment failure and the development of precision medicine strategies. Generation of genetic models that more accurately reflect the normal developmental history of T-ALL are necessary to identify new avenues for treatment. The DNA methyltransferase enzyme DNMT3A is also recurrently mutated in T-ALL patients, and we show here that inactivation of Dnmt3a combined with Notch1 gain-of-function leads to an aggressive T-ALL in mouse models. Moreover, conditional inactivation of Dnmt3a in mouse hematopoietic cells leads to an accumulation of immature progenitors in the thymus which are less apoptotic. These data demonstrate that Dnmt3a is required for normal T-cell development, and acts as a T-ALL tumor suppressor.

PHF6 and DNMT3A mutations are enriched in distinct subgroups of mixed phenotype acute leukemia with T-lineage differentiation

“…[49][50][51][65][66][67] DNMT3A also functions as a tumor suppressor in T-ALL and DNMT3A mutations are frequent in ETP-ALL. 48,68 Whether DNMT3A mutations drive the pathogenesis of MPAL remains to be clarified. DNMT3A-mutated MPAL commonly acquires comutations (IDH2 and RAS) common in AML, suggesting that this subset of MPAL shares pathogenetic similarity to AML.…”

Cost‐effective screening of DNMT3A coding sequence identifies somatic mutation in pediatric T‐cell acute lymphoblastic leukemia

“…Several studies on DNMT3A in other hematological malignancies show that a substantial proportion of mutations also affect Pro‐Trp‐Trp‐Pro (PWWP) and ATRX‐DNMT3‐DNMT3L (ADD) domains, both responsible for chromatin binding and interactions with other proteins. Ultimately, studying the sequence of all exons coding the three domains, MTase, PWWP, and ADD, is necessary to unravel the mutational status of the DNMT3A gene. Our genotyping approach (combined Sanger sequencing and HRM) covers all crucial coding domains and a cost‐effective alternative to NGS to analyze mutational status of DNMT3A coding sequence in hematological malignancies.…”

“…Given the crucial role of DNMT3A activity in DNA methylation during hematopoiesis, its putative tumor suppressor role in T‐ALL and the aberrant methylation pattern observed in T‐ALL patients, we hypothesized that DNMT3A mutations represent a leukemogenic event and confer prognostic significance in pediatric T‐ALL. To address this hypothesis, we included DNMT3A as a candidate, in the panel of 25 selected genes, established T‐ALL “drivers,” that we assessed for the prognostic significance in pediatric T‐ALL in the context of International Berlin‐Frankfurt‐Munster (I‐BFM) treatment protocol (Szarzyńska‐Zawadzka B. et al, unpublished).…”

Variants ofDNMT3Acause transcript-specific DNA methylation patterns and affect hematopoietic differentiation

“…S1D). Recent findings also indicate that Dnmt3a is relevant for normal thymocyte maturation (Kramer et al 2017).…”