BCR-ABL SH3-SH2 domain mutations in chronic myeloid leukemia patients on imatinib.
Point mutations in the kinase domain of BCR-ABL are the most common mechanism of drug resistance in chronic myeloid leukemia (CML) patients treated with ABL kinase inhibitors, including imatinib. It has also been shown in vitro that mutations outside the kinase domain in the neighboring linker, SH2, SH3, and Cap domains can confer imatinib resistance. In the context of ABL, these domains have an autoinhibitory effect on kinase activity, and mutations in this region can activate the enzyme. To determine the frequency and relevance to resistance of regulatory domain mutations in CML patients on imatinib, we screened for such mutations in a cohort of consecutive CML patients with various levels of response. Regulatory domain mutations were detected in 7 of 98 patients, whereas kinase domain mutations were detected in 29. One mutation (T212R) conferred in vitro tyrosine kinase inhibitor resistance and was associated with relapse, whereas most other mutations did not affect drug sensitivity. Mechanistic studies showed that T212R increased the activity of ABL and BCR-ABL and that T212R-induced resistance may be partially the result of stabilization of an active kinase conformation. Regulatory domain mutations are uncommon but may explain resistance in some patients without mutations in the kinase domain.
Sherbenou
Daniel W
DW
Cell and Developmental Biology, Oregon Health & Science University, Portland, OR, USA.
Hantschel
Oliver
O
Kaupe
Ines
I
Willis
Stephanie
S
Bumm
Thomas
T
Turaga
Lalita P
LP
Lange
Thoralf
T
Dao
Kim-Hien
KH
Press
Richard D
RD
Druker
Brian J
BJ
Superti-Furga
Giulio
G
Deininger
Michael W
MW
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001549:Benzamides; D002460:Cell Line; D015331:Cohort Studies; D019008:Drug Resistance, Neoplasm; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation; D010879:Piperazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011494:Protein Kinases / Q000378:metabolism; D011743:Pyrimidines / Q000627:therapeutic use*; D055815:Young Adult; D018909:src Homology Domains
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011494:Protein Kinases; D016044:Fusion Proteins, bcr-abl