A gene expression signature of CD34+ cells to predict major cytogenetic response in chronic-phase chronic myeloid leukemia patients treated with imatinib

Shannon K. McWeeney, Lucy C. Pemberton, Marc M. Loriaux, Kristina Vartanian, Stephanie G. Willis, Gregory Yochum, Beth Wilmot, Yaron Turpaz, Raji Pillai, Brian J. Druker, Jennifer L. Snead, Mary MacPartlin, Stephen G. O'Brien, Junia V. Melo, Thoralf Lange, Christina A. Harrington, Michael W.N. Deininger

Research output: Contribution to journalArticle

85 Scopus citations

Abstract

In chronic-phase chronic myeloid leukemia (CML) patients, the lack of a major cytogenetic response (< 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 2 independent cohorts of imatinib-naive chronic-phase CML patients. The learning set consisted of retrospectively selected patients with a complete cytogenetic response or more than65%Ph + metaphases within 12 months of imatinib therapy.Basedonanalysis of varianceP less than .1 and fold difference 1.5 or more, we identified 885 probe sets with differential expression between responders and nonre-sponders, from which we extracted a 75-probe set minimal signature (classifier) that separated the 2 groups. On application to a prospectively accrued validation set, the classifier correctly predicted 88% of responders and83% of nonresponders. Bioinformatics analysis and comparison with published studies revealed overlap of classifier genes withCMLprogression signatures and implicated β-catenin in their regulation, suggesting that chronic-phase CML patients destined to fail imatinib have more advanced disease than evident by morphologic 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.

Original languageEnglish (US)
Pages (from-to)315-325
Number of pages11
JournalBlood
Volume115
Issue number2
DOIs
StatePublished - Jan 14 2010

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    McWeeney, S. K., Pemberton, L. C., Loriaux, M. M., Vartanian, K., Willis, S. G., Yochum, G., Wilmot, B., Turpaz, Y., Pillai, R., Druker, B. J., Snead, J. L., MacPartlin, M., O'Brien, S. G., Melo, J. V., Lange, T., Harrington, C. A., & Deininger, M. W. N. (2010). A gene expression signature of CD34+ cells to predict major cytogenetic response in chronic-phase chronic myeloid leukemia patients treated with imatinib. Blood, 115(2), 315-325. https://doi.org/10.1182/blood-2009-03-210732