Properties of CD34+ CML stem/progenitor cells that correlate with different clinical responses to imatinib mesylate.
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.
Jiang
Xiaoyan
X
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada. xjiang@bccrc.ca
Forrest
Donna
D
Nicolini
Franck
F
Turhan
Ali
A
Guilhot
Joelle
J
Yip
Calvin
C
Holyoake
Tessa
T
Jorgensen
Heather
H
Lambie
Karen
K
Saw
Kyi Min
KM
Pang
Emily
E
Vukovic
Ranko
R
Lehn
Paeta
P
Ringrose
Ashley
A
Yu
Miao
M
Brinkman
Ryan R
RR
Smith
Clay
C
Eaves
Allen
A
Eaves
Connie
C
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
D018952:Antigens, CD34; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate