Properties of CD34+ CML stem/progenitor cells that correlate with different clinical responses to imatinib mesylate

Jiang, X. et al. (2010) Properties of CD34+ CML stem/progenitor cells that correlate with different clinical responses to imatinib mesylate. Blood, 116(12), pp. 2112-2121. (doi: 10.1182/blood-2009-05-222471)

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Publisher's URL: http://dx.doi.org/10.1182/blood-2009-05-222471

Abstract

Imatinib mesylate (IM) induces clinical remissions in chronic-phase chronic myeloid leukemia (CML) patients but IM resistance remains a problem. We recently identified several features of CML CD34<sup>+</sup> stem/progenitor cells expected to confer resistance to <em>BCR-ABL</em>-targeted therapeutics. From a study of 25 initially chronic-phase patients, we now demonstrate that some, but not all, of these parameters correlate with subsequent clinical response to IM therapy. CD34<sup>+</sup> cells from the 14 IM nonresponders demonstrated greater resistance to IM than the 11 IM responders in colony-forming cell assays in vitro (<em>P</em> < .001) and direct sequencing of cloned transcripts from CD34<sup>+</sup> cells further revealed a higher incidence of <em>BCR-ABL</em> kinase domain mutations in the IM nonresponders (10%-40% vs 0%-20% in IM responders, <em>P</em> < .003). In contrast, CD34<sup>+</sup> cells from IM nonresponders and IM responders were not distinguished by differences in <em>BCR-ABL</em> or transporter gene expression. Interestingly, one <em>BCR-ABL</em> mutation (V304D), predicted to destabilize the interaction between p210<sup>BCR-ABL</sup> and IM, was detectable in 14 of 20 patients. T315I mutant CD34<sup>+</sup> cells found before IM treatment in 2 of 20 patients examined were preferentially amplified after IM treatment. Thus, 2 properties of pretreatment CML stem/progenitor cells correlate with subsequent response to IM therapy. Prospective assessment of these properties may allow improved patient management.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Holyoake, Professor Tessa and Jorgensen, Dr Heather
Authors: Jiang, X., Forrest, D., Nicolini, F., Turhan, A., Guilhot, J., Yip, C., Holyoake, T., Jorgensen, H., Lambie, K., Saw, K.M., Pang, E., Vukovic, R., Lehn, P., Ringrose, A., Yu, M., Brinkman, R.R., Smith, C., Eaves, A., and Eaves, C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Blood
ISSN:0006-4971

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