Ezh2 loss in hematopoietic stem cells predisposes mice to develop heterogeneous malignancies in an Ezh1-dependent manner

Abstract

Key Points Ezh2 loss in hematopoietic stem cells predisposes mice to develop heterogeneous hematologic malignancies. Ezh1 is essential to maintain hematopoiesis in the setting of Ezh2 loss.

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.…”

The roles of Polycomb group proteins in hematopoietic stem cells and hematological malignancies

“…This functional duality of Ezh2 has also been demonstrated in experiments in mouse models. Several experiments in which mice were observed long-term after loss of Ezh2 in hematopoietic cells showed that this loss leads to development of heterogeneous malignancies including T-ALL, MDS, and MDS/MPN [84][85][86]. These results indicate that Ezh2 functions as a tumor suppressor gene in the pathogenesis of T-ALL and MDS-related diseases.…”

Multifaceted role of the polycomb-group gene EZH2 in hematological malignancies

“…Ezh2-deficient hematopoietic cells develop MDS and MDS/MPN-like diseases in mice, but not AML even in serially transplantation [9,37], implying an oncogenic property of EZH2 in the pathogenesis of AML. In fact, deletion of Ezh2 resulted in significantly reduced leukemia-initiating cells and enhanced differentiation of leukemic cells in a mouse model of MLL-AF9 induced AML.…”

“…In contrast, Ezh2 is dispensable for self-renewal of HSCs due to the compensatory function of Ezh1. Ezh1-containing PRC2 (Ezh1-PRC2) co-regulates a large number of target genes with Ezh2-containing PRC2 (Ezh2-PRC2) and, notably, is redistributed to a significant portion of Ezh2-specific targets on the loss of Ezh2 [7,9,10]. On overexpression, Ezh2 efficiently prevents exhaustion of the long-term repopulating potential of HSCs during repeated serial transplantation [11].…”

“…Although over-expression and gain-of-function mutations of EZH2 play oncogenic roles in the development of Mochizuki-Kashio et al [9] ETP-ALL Ezh2…”