Loss of G0S2 in Kinase-Independent TKI Resistance and Blastic Transformation of CML

Abstract Tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 have turned chronic myeloid leukemia (CML) from a fatal to a chronic condition. Despite impressive results, resistance is a clinical problem, and TKIs do not target the CML leukemic stem cell (LSC) population, which is independent of BCR-ABL1 kinase activity. To identify mechanisms associated with BCR-ABL1 kinase-independent TKI resistance, we compared the transcriptional profile of TKI-naive CD34+ cells from newly diagnosed CML patients who subsequently either responded (n=41) or did not respond (n=18) to imatinib over a twelve-month period (McWeeney et al. Blood 2010). The transcriptional profile of imatinib resistance in non-responders revealed striking overlap with reported signatures of CML blastic transformation and also implicated pathways involved in LSC survival. These findings suggest that similar biological mechanisms may be driving three different scenarios of BCR-ABL1-independent resistance: 1) primary kinase-independent TKI resistance, 2) transformation of CML from the chronic phase (CP-CML) to the blastic phase (BP-CML), and 3) persistence of residual leukemia in TKI-responsive patients. Among the genes most profoundly downregulated in patients destined to fail imatinib therapy was G0S2 (>3-fold, p 3-fold in TKI-resistant samples and BP-CML (p Altogether, these findings suggest that G0S2 plays a role in regulating leukemic stem and progenitor cell survival and TKI response in vitro, and that restoring G0S2 expression combined with BCR-ABL1 inhibition may be a novel strategy to induce treatment-free remission in CML patients with kinase-independent TKI resistance and BP-CML, or to eradicate the CML LSC population. Future studies will assess the functional role of G0S2 in LSC survival and BCR-ABL1 leukemogenesis in vivo, and determine the mechanism by which G0S2 is downregulated in TKI resistance. Disclosures Deininger: BMS: Consultancy, Research Funding; Ariad Pharmaceuticals, Bristol Myers Squibb, CTI BioPharma Corp, Gilead, Incyte, Novartis, Pfizer, Celgene, Blue Print, Galena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Celgene: Research Funding; Gilead: Research Funding; ARIAD: Consultancy.