The Philadelphia (Ph) 9;22 chromosome translocation has two common isoforms that are preferentially associated with distinct subtypes of leukemia. The p210 variant is the hallmark of CML whereas p190 is frequently associated with B-ALL. The only sequence difference between the two isoforms is the guanidine exchange factor (GEF) domain. This GEF is reported to activate RHO family GTPases in response to diverse extracellular stimuli. It is not clear whether and how RHOA contributes to the p210 CML progression. Here we show that knockout of RHOA in the K562 and KU812, p210-expressing cell lines leads to suppression of leukemogenesis in animal models in vivo. RNA-Seq analysis of the mock control and null cells demonstrates a distinct change in the gene expression profile as a result of RHOA deletion, with significant down regulation of genes involved in cell activation and cell adhesion. Cellular analysis revealed that RHOA knockout leads to impaired cell adhesion and migration, and most importantly, the homing ability of leukemia cells to the bone marrow, which may be responsible for the attenuated leukemia progression. We also identified IGFBP2 as an important downstream target of RHOA. Further mechanistic investigation shows RHOA activation leads to relocation of the serum response factor (SFR) into the nucleus, where it directly activates IGFBP2. Knockout of IGFBP2 in CML cells suppresses cell adhesion/invasion, as well as leukemogenesis in vivo. This elevated IGFBP2 expression is confirmed in primary CML samples. Thus, we demonstrate one mechanism whereby RHOA-SRF-IGFBP2 signaling axis contributes to development of leukemia in cells expressing the p210 BCRABL1 fusion kinase.
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