title: Properties of CD34+ CML stem/progenitor cells that correlate with different clinical responses to imatinib mesylate.
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 BCR-ABL-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 (P < .001) and direct sequencing of cloned transcripts from CD34(+) cells further revealed a higher incidence of BCR-ABL kinase domain mutations in the IM nonresponders (10%-40% vs 0%-20% in IM responders, P < .003). In contrast, CD34(+) cells from IM nonresponders and IM responders were not distinguished by differences in BCR-ABL or transporter gene expression. Interestingly, one BCR-ABL 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.
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada. xjiang@bccrc.ca
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Jiang
authors.forename: Donna
authors.initials: D
authors.lastname: Forrest
authors.forename: Franck
authors.initials: F
authors.lastname: Nicolini
authors.forename: Ali
authors.initials: A
authors.lastname: Turhan
authors.forename: Joelle
authors.initials: J
authors.lastname: Guilhot
authors.forename: Calvin
authors.initials: C
authors.lastname: Yip
authors.forename: Tessa
authors.initials: T
authors.lastname: Holyoake
authors.forename: Heather
authors.initials: H
authors.lastname: Jorgensen
authors.forename: Karen
authors.initials: K
authors.lastname: Lambie
authors.forename: Kyi Min
authors.initials: KM
authors.lastname: Saw
authors.forename: Emily
authors.initials: E
authors.lastname: Pang
authors.forename: Ranko
authors.initials: R
authors.lastname: Vukovic
authors.forename: Paeta
authors.initials: P
authors.lastname: Lehn
authors.forename: Ashley
authors.initials: A
authors.lastname: Ringrose
authors.forename: Miao
authors.initials: M
authors.lastname: Yu
authors.forename: Ryan R
authors.initials: RR
authors.lastname: Brinkman
authors.forename: Clay
authors.initials: C
authors.lastname: Smith
authors.forename: Allen
authors.initials: A
authors.lastname: Eaves
authors.forename: Connie
authors.initials: C
authors.lastname: Eaves
mesh_terms: D000328:Adult; D000368:Aged; D018952:Antigens, CD34; D001549:Benzamides; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D011379:Prognosis; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D013234:Stem Cells / Q000187:drug effects; D055815:Young Adult
chemical_list: D018952:Antigens, CD34; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate