The new findings in molecular mechanism of DNMT3A mutation-related leukemia and potential therapeutic targets

According to the researchers from Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine and Shanghai Institute of Hematology, by using a conditional knockin approach in mice, their study shows that DNA methyltransferase DNMT3A R878H mutation gene is sufficient to initiate AML (Acute myeloid leukemia), and mTOR pathway is activated improperly, which can be a potential therapeutic target. The findings were published online on May 1 in the Proceedings of the National Academy of Sciences of the United States( PNAS), andProfessor Zhu Chenand Sai-Juan Chen and Researcher Yue-Ying Wang are the co-authors of this paper.

As early as in 2011, this group identifiedhigh-frequency mutations in the DNMT3A in patients with acute mononuclear leukemia, which provides a new molecular marker for the diagnosis and prognosis evaluation of AML due to its association with poor prognosis. This article has been published in Nature Genetics. Then, the group constructed the mice models with DNMT3A-R882H mutation by using retroviral transduction and bone marrow transplantation (BMT) technology, which reveals the mutation can affect the DNA methylation ofleukemia-related genes, and thus increases their expression, including the Hox family, Idh1, Hlf, Flt3 and Mpl, and eventually leads to tchronic myelomonocytic leukemia (CMML) in mice. The studyhas also been published in PNAS in 2014.

In recent years, the team has built the mice model with conditional knockin of Dnmt3a R878H (Dnmt3a R882H in human) by the embryonic microinjection technology to further study how Dnmt3a mutations lead to leukemia under the control of endogenous promoters and enhancers. It was found that the genetic changes of Dnmt3a mutation could induce abnormal proliferation of hematopoietic stem/progenitor cells and then initiate AML in mice, while the leukemia originated cells are mainly LSK (Lin? Sca1+cKit +) hematopoietic stem/progenitor cells. Through the study in leukemia cell tranome and DNA methylation spectrum, and RNA sequencing analysis of leukemia stem/progenitor cells of single cell, it reveals the Dnmt3a R878H mutations could cause significant changes of genetic expression and epigenetic regulation patterns, leading to the blockage of proliferation and excessive differentiation in hematopoietic cells. The study also found that CDK1, a key cyclin,was up-regulated due to mTOR activation associated with DNA hypomethylationto promote the proliferation of hematopoietic cells. Moreover, overexpressed CDK1-mediated EZH2 phosphorylation resulted in an abnormal trimethylation of H3K27 profile. Based on these results, by using rapamycin, amTOR‘s specific inhibitor, the researchersfound that it could significantly inhibit the proliferation of leukemia cells, and significantly alleviated the symptoms of leukemia and prolonged survival in mice, suggesting that the abnormal activation of mTOR maybecome a potential drug target. Therefore, the combined application of mTOR inhibitor could significantly improve the therapeutic effect in patientswith DNMT3A mutated-related AML.

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