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)

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⁺ 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⁺ 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⁺ 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⁺ 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^BCR-ABL and IM, was detectable in 14 of 20 patients. T315I mutant CD34⁺ 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 > School of Cancer Sciences
• Journal Name: Blood
• ISSN: 0006-4971