Concurrent loss of Ezh2 and Tet2 cooperates in the pathogenesis of myelodysplastic disorders

Abstract

Deletion of Ezh2 results in transcriptional repression of developmental regulator genes, derepression of oncogenic polycomb targets, and induction of MDS/MPN-like disease in mice that is exacerbated by concurrent deletion of Tet2.

Epigenetic dysregulation of hematopoietic stem cells and preleukemic state

“…Recent study has demonstrated cooperative function of Tet2 loss and Flt3 ITD mutations in AML development in vivo through combinatorial epigenetic remodeling of specific genetic loci [73]. In agreement with co-occurrence of TET2 and EZH2 mutations in MDS and MDS/MPN patients, concurrent depletion of Tet2 and Ezh2 in mice developed MDS or MDS/MPN by derepression of oncogenic polycomb targets [74]. In addition, combined Tet2 loss with AML1-ETO leads to fully penetrant AML in vivo, partially due to hypermethylation of enhancer regions thereby silencing tumor suppressors [59,75].…”

Hmga2 collaborates with JAK2V617F in the development of myeloproliferative neoplasms

“…Figure 5B-C; supplemental Table 2), and that 35 genes, including known oncogenes targeted by Ezh2, Lmo1, Gcat, and Prss16, 44 were common ( Figure 5D). There were some commonly enriched gene sets, including those involved in activation of the MYC pathway between ΔHmga2/JAK2 V617F and JAK2…”

Molecular determinants of pathogenesis and clinical phenotype in myeloproliferative neoplasms

“…In contrast to EZH2 mutations seen in lymphoma, those in MPNs tend to be loss-of-function mutations 75 that result in the derepression of a set of genes that includes a number of putative oncogenes (e.g., LMO1 and HOXA9), and are associated with increased HSC self-renewal. 76,77 Mutations of additional sex combs like 1 (ASXL1) are also relatively common in MF. 78 ASXL1, a component of PRC1, is also known to regulate PRC2 and to have a role in the regulation of HOX genes.…”