Tumor suppressor role of Ezh2 in an NRASQ61K driven model of Early T-cell Precursor Acute Lymphoblastic Leukemia (RNA-Seq)

Purpose: To characterize transcriptional changes associated with homozygous inactivation the Polycomb Repressive Complex 2 (PRC2) lysine methyltransferase Ezh2 in a mouse model of earlt T-cell precursor ALL (ETP-ALL) Methods: We sequenced mRNA from NRASQ61K transformed murine LSK-cells co-transduced with a self-inactivating Cre-vector. Cells were sorted for Cre-expression (lox-stop-loxRosa26-YFP) or expression of an inert control vector (GFP) and differentiated on OP9DL1 stroma with and without a functional Ezh2 gene. Results: Inactivation of Ezh2 in this model leads to accelerated leukemia development. Resulting gene expression changes are complex and include enrichment of genes associated with immature hematopoietic cells, Ras signaling and Cytokines and their cognate receptors. Conclusions: Inactivation of Ezh2 in our model leads to accentuated expression of early hematopoietic gene expression programs and to accentuated growth and survival signaling. Overall design: Examination of mRNA levels between Ezh2ff and Ezh2ko in vivo, Ezh2ff and Ezh2ko in vitro.

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Danis E, Yamauchi T, Echanique K, Zhang X, Haladyna JN, Riedel SS, Zhu N, Xie H, Orkin SH, Armstrong SA, Bernt KM, Neff T