A gene expression signature of CD34+ cells to predict major cytogenetic response in chronic-phase chronic myeloid leukemia patients treated with imatinib.
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 than 65% Ph(+) metaphases within 12 months of imatinib therapy. Based on analysis of variance P less than .1 and fold difference 1.5 or more, we identified 885 probe sets with differential expression between responders and nonresponders, 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 and 83% of nonresponders. Bioinformatics analysis and comparison with published studies revealed overlap of classifier genes with CML progression signatures and implicated beta-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.
McWeeney
Shannon K
SK
Oregon Health & Science University Knight Cancer Institute, Portland, OR 97239, USA.
Pemberton
Lucy C
LC
Loriaux
Marc M
MM
Vartanian
Kristina
K
Willis
Stephanie G
SG
Yochum
Gregory
G
Wilmot
Beth
B
Turpaz
Yaron
Y
Pillai
Raji
R
Druker
Brian J
BJ
Snead
Jennifer L
JL
MacPartlin
Mary
M
O'Brien
Stephen G
SG
Melo
Junia V
JV
Lange
Thoralf
T
Harrington
Christina A
CA
Deininger
Michael W N
MW
D000328:Adult; D000368:Aged; D018952:Antigens, CD34 / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001549:Benzamides; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D010677:Philadelphia Chromosome / Q000187:drug effects; D010879:Piperazines / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*
D018952:Antigens, CD34; D000970:Antineoplastic Agents; D001549:Benzamides; D009363:Neoplasm Proteins; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate