High expression of ABCG2 induced by EZH2 disruption has pivotal roles in MDS pathogenesis

Abstract

Both proto-oncogenic and tumor-suppressive functions have been reported for enhancer of zeste homolog 2 (EZH2). To investigate the effects of its inactivation, a mutant EZH2 lacking its catalytic domain was prepared (EZH2-dSET). In a mouse bone marrow transplant model, EZH2-dSET expression in bone marrow cells induced a myelodysplastic syndrome (MDS)-like disease in transplanted mice. Analysis of these mice identified Abcg2 as a direct target of EZH2. Intriguingly, Abcg2 expression alone induced the same disease in the transplanted mice, where stemness genes were enriched. Interestingly, ABCG2 expression is specifically high in MDS patients. The present results indicate that ABCG2 de-repression induced by EZH2 mutations have crucial roles in MDS pathogenesis.

MDS cells impair osteolineage differentiation of MSCs via extracellular vesicles to suppress normal hematopoiesis

“…We also found that ABCG2 expression is upregulated explicitly in MDS patients regardless of the presence of EZH2 mutation (Kawabata et al, Article ll 2018). Although serially transplanted recipients with Abcg2-expressing cells developed a MDS overt AML-like disease (MDS/ AML hereafter), these mice exhibited hypoplasia of the BM with predominant MDS/AML cells (Figures 1A and 1B), in which we confirmed morphological abnormalities (Figure S1A), decreased self-renewal and colony output of HSCs, lower proliferation rate in vitro, and increased apoptosis (Kawabata et al, 2018) and that the MDS/AML cells divided more slowly than control BM cells in vitro (Figure S1B). Consistently, histological analysis showed lower Ki-67 + proliferative BM cells compared with controls (Figure S1C).…”

“…We previously demonstrated that a loss-of-function EZH2 mutant harboring the deletion of the SET domain derepressed ABCG2 via reduction of a repressive mark, H3K27me3, and that the ectopic expression of Abcg2 induced a MDS-like phenotype in a transplant model (Kawabata et al, 2018). We also found that ABCG2 expression is upregulated explicitly in MDS patients regardless of the presence of EZH2 mutation (Kawabata et al, Article ll 2018).…”

“…We utilized the hypoplastic Abcg2-expressing model and the hyperplastic NHD13Tg model, both of which faithfully recapitulated human MDS, to analyze the interaction between MDS cells and the altered BM microenvironment (Kawabata et al, 2018;Lin et al, 2005). It is noteworthy that both MDS models disturbed the cell fate of the surrounding stromal cells and impaired the supportive role of MSCs in hematopoiesis via mEVs regardless of the cellularity of MDS cells.…”

“…First, we considered the possibility of a dysregulated production of chemokines and cytokines secreted from MDS/AML cells. However, our previous transcriptome analysis did not detect significant alterations in chemokines reported to suppress osteogenesis such as Ccl3 (Kawabata et al, 2018;Vallet et al, 2011). Given that EVs derived from MDS/AML cells are critical mediators of intercellular communication (Horiguchi et al, 2016) and that EVs are aberrantly increased in a variety of cancers (Andre et al, 2002;Bergmann et al, 2009;Kumar et al, 2017), we inspected whether EVs from MDS/AML cells were incorporated into the MSCs.…”

Deciphering the Therapeutic Resistance in Acute Myeloid Leukemia

“…ABCG2 was identified as a new target of the PRC2 complex. More importantly ABCG2 is a stem cell marker and drug efflux transporter rendering cancer cells resistant to chemotherapeutic drugs [ 43 ]. Overexpression of ABC P-gp transporters, has also been shown to be related to FLT3 -ITD and not only to EZH2 mutations, possibly driving refractory to chemotherapeutic agents and depressing their sensitivity several hundred times [ 21 , 44 , 45 ].…”