A Gene Expression Signature of CD34+ Cells to Predict Major Cytogenetic Response in Chronic Phase Chronic Myeloid Leukemia Patients Treated with Imatinib: Potential Involvement of Beta-Catenin in Drug Resistance.
Authors: McWeeney Shannon , Yochum Gregory , Pemberton Lucy C. , Loriaux Marc , Vartanian Kristina , Willis Stephanie G , Wilmot Beth , Turpaz Yaron , Pillai Raji , partlin Mary Mac , Snead Jennifer , Druker Brian J. , O'Brien Stephen G , Melo Junia V. , Lange Thoralf , Harrington Christina , Deininger Michael 
Published: October 2019

Abstract
Abstract 508
In chronic phase chronic myeloid leukemia (CML) patients the lack of a major cytogenetic response (MCyR, <36% Ph+ metaphases) to imatinib within 12 months indicates failure and mandates a change of therapy. To identify biomarkers predictive of imatinib failure we performed gene expression array profiling of CD34+ cells from two independent cohorts of imatinib-naïve chronic phase CML patients. The learning set consisted of retrospectively selected patients with a complete cytogenetic response (CCyR) or >65% Ph-positive metaphases within 12 months of imatinib therapy. Based on ANOVA p<0.1 and fold difference >I1.5I we identified 885 probe sets with differential expression between responders and non-responders, from which we extracted a 75-probe set minimal signature (classifier) that separated the two groups. Upon application to a prospectively accrued validation set, the classifier correctly predicted 88% of responders and 83% of non-responders. Bioinformatics analysis and comparison with published studies revealed highly significant overlap of the resistance signature with CML progression signatures. Consistent with this, differential expression of selected resistance genes was confirmed by qPCR on CD34+ cells from an independent set of patients with chronic phase vs. blast crisis. Furthermore, upon analysis of promoter sequences and comparison with a library of physical beta-catenin targets [generated by serial analysis of chromatin occupancy (SACO) in the HCC-116 colon cancer cell line] we find evidence that b-catenin may be a master regulator of resistance genes. Consistent with this, preliminary chromatin immunoprecipitation (ChIP) data on primary cells support physical beta-catenin binding to selected resistance genes, suggesting that Wnt/beta-catenin activation may be involved in primary cytogenetic resistance as well as disease progression.

Conclusion:
Our data suggest that chronic phase CML patients destined to fail imatinib have more advanced disease than evident by morphological criteria. Our classifier may allow directing more aggressive therapy upfront to the patients most likely to benefit, while sparing good-risk patients from unnecessary toxicity. The potential role of beta-catenin in the regulation of resistance genes suggests that targeting Wnt/beta-catenin signaling may be useful to overcome resistance.

Disclosures:
Druker: MolecularMD: Equity Ownership; Novartis Pharmaceuticals: ; Bristol-Myers Squibb: . O'Brien:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Wyeth: Research Funding. Deininger:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Calistoga: Research Funding; Genzyme: Research Funding.