Ezh2 loss promotes development of myelodysplastic syndrome but attenuates its predisposition to leukaemic transformation

Abstract

Loss-of-function mutations of EZH2, a catalytic component of polycomb repressive complex 2 (PRC2), are observed in B10% of patients with myelodysplastic syndrome (MDS), but are rare in acute myeloid leukaemia (AML). Recent studies have shown that EZH2 mutations are often associated with RUNX1 mutations in MDS patients, although its pathological function remains to be addressed. Here we establish an MDS mouse model by transducing a RUNX1S291fs mutant into hematopoietic stem cells and subsequently deleting Ezh2. Ezh2 loss significantly promotes RUNX1S291fs-induced MDS. Despite their compromised proliferative capacity of RUNX1S291fs/Ezh2-null MDS cells, MDS bone marrow impairs normal hematopoietic cells via selectively activating inflammatory cytokine responses, thereby allowing propagation of MDS clones. In contrast, loss of Ezh2 prevents the transformation of AML via PRC1-mediated repression of Hoxa9. These findings provide a comprehensive picture of how Ezh2 loss collaborates with RUNX1 mutants in the pathogenesis of MDS in both cell autonomous and non-autonomous manners.

Loss of Ezh2 cooperates with Jak2V617F in the development of myelofibrosis in a mouse model of myeloproliferative neoplasm

“…35,36 In contrast, deletion of Ezh2 in mouse hematopoietic compartments results in T-cell acute leukemia 37 and MDS-like phenotype. 38 Furthermore, loss of Ezh2 cooperates with Tet2 deficiency 39 or RUNX1 mutation 40 in the development of MDS. Interestingly, Ezh2 knock-in mice overexpressing Ezh2 in hematopoietic cells develop MPN-like disease.…”

Overexpression of the shortest isoform of histone demethylase LSD1 primes hematopoietic stem cells for malignant transformation

“…Similar initiator functions have been demonstrated in other epigenetic regulators, such as the methylcytosine hydroxylase TET2, histone methyltransferase EZH2, and Polycomb-related protein ASXL2, in myeloid leukemogenesis. [7][8][9][10] However, it is still unknown whether this theory is applicable to other malignancies.…”

Epigenetic regulation of miRNA-124 and multiple downstream targets is associated with treatment response in myeloid malignancies

“…Notably, EZH2, a histone methyl transferase, has been identified to mediate oncogenic and tumor suppressor effects in myeloid malignancies (1,17). Inactivating mutations of EZH2 have been identified in MDS (1), whilst loss of function mutations in EZH2 are also associated with a decreased rate of progression to AML (18). EZH2 upregulation has also been identified Figure 3.…”