Induction of mutant Npm1 after development of Dnmt3a-mutant CH causes progression to myeloproliferative disorder (MPD), and more aggressive MPD is observed with longer latency between mutations.
These findings identify oncogenic cooperativity between Jak2V617F-driven MPN and Dnmt3a loss, leading to activation of HSPC enhancer-driven inflammatory signaling.
Some other genes' location such as TET oncogene family member 2 (TET2), additional sex combs-like 1 (ASXL1), casitas B-lineage lymphoma proto-oncogene (CBL), isocitrate dehydrogenase 1/2 (IDH1/IDH2), IKAROS family zinc finger 1 (IKZF1), DNA methyltransferase 3A (DNMT3A), suppressor of cytokine signaling (SOCS), enhancer of zeste homolog 2 (EZH2), tumor protein p53 (TP53), runt-related transcription factor 1 (RUNX1) and high mobility group AT-hook 2 (HMGA2) have also identified to be involved in MPNs phenotypes.
Mutations in the human DNA methyl transferase 3A (DNMT3A) gene are recurrently identified in several hematologic malignancies such as Philadelphia chromosome-negative myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS), MPN/MDS overlap syndromes and acute myeloid leukemia (AML).
In this Review we discuss recent genetic and functional data implicating mutations in epigenetic modifiers, including tet methylcytosine dioxygenase 2 (TET2), isocitrate dehydrogenase 1 (IDH1), IDH2, additional sex combs-like 1 (ASXL1), enhancer of zeste homologue 2 (EZH2) and DNA methyltransferase 3A (DNMT3A), in the pathogenesis of MPN, MDS and AML, and discuss how this knowledge is leading to novel clinical, biological and therapeutic insights.