Abstract 648: Role of G0S2 in chronic myeloid leukemia and TKI resistance

• Published in: Cancer research (Chicago, Ill.) Ill.), 2020-08, Vol.80 (16_Supplement), p.648-648
• Main Authors: Gonzalez, Mayra A., Bencomo, Alfonso E., Barreto-Vargas, Christian, Rubio, Andres J., Olivas, Idaly M., Lara, Joshua J., Senina, Anna, Ahmann, Jonathan, Varley, Katherine T., Jave-Suarez, Luis F., Thomas, O'Hare, Deininger, Michael W., Eiring, Anna M.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2020-648

Tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 have turned chronic myeloid leukemia (CML) from a fatal to a chronic disease. However, resistance is a clinical problem, and TKIs do not target CML leukemic stem cells (LSC), which are independent from BCR-ABL1 kinase activity. To understand mechanisms driving BCR-ABL1-independent resistance, we analyzed the transcriptional signature of TKI-naïve CD34+ cells from patients with or without a response to imatinib after 12 months of therapy (McWeeney et al. Blood 2010). Among the genes most profoundly downregulated in patients destined to fail imatinib was G0/G1 switch gene 2 (G0S2) (>3-fold, n=59, p50%) correlated with a longer overall survival (n=30 responders, n=16 non-responders, p=0.036). We next analyzed G0S2 mRNA expression in CD34+ cells from normal cord blood and from primary CD34+ cells lacking BCR-ABL1 kinase domain mutations. G0S2 was 4-fold downregulated in newly diagnosed CML (n=6) compared to normal cord blood (n=5, p3-fold in TKI-resistant (n=2) and BP-CML samples (n=5, p