The Tumor Suppressors, Ms4a3 And G0s2, Are Downregulated In Cml Cells With Bcr-Abl1 Kinase-Independent Resistance

Background: The treatment and survival of chronic myeloid leukemia (CML) patients has greatly improved after the discovery of imatinib; however, disease persistence and drug resistance remain as clinical problems. McWeeney et al. (Blood 2010;115:315-325) identified a gene expression signature predictive of primary cytogenetic resistance to imatinib in treatment-naïve CML chronic phase (CML-CP) patients lacking BCR-ABL1 kinase domain mutations. Comparison of this gene classifier with other studies revealed extensive overlap of resistance genes with genes associated with CML blastic transformation, suggesting that CML-CP patients destined to fail imatinib may exhibit a gene profile reminiscent of advanced CML. Based on rank predictive score from the microarray, the top transcripts found to be dysregulated in newly diagnosed patients who subsequently emerged as imatinib non-responders were: PLCXD2, EGF16, GAS2, RXFP1, ITGA2, MS4A3, FCN1, EMCN, EMCN, CLIP4, ZNF44 and G0S2. Among these, MS4A3 and G0S2 were differentially downregulated in non-responders compared to responders. Conversely, high levels of MS4A3 (p=0.059) and G0S2 (p=0.036) correlated with higher likelihood of major cytogenetic response and longer overall survival. MS4A3 (HTM4) is a hematopoietic cell cycle regulator that inhibits G1/S phase cell cycle transition, whereas G0S2 is proapoptotic mitochondrial protein that interacts with and antagonizes BCL-2. In this study, we investigated the potential role of MS4A3 and G0S2 as tumor suppressors in CML and their influence on TKI resistance and blastic transformation.