Ph(+) acute lymphoblastic leukemia resistant to the tyrosine kinase inhibitor STI571 has a unique BCR-ABL gene mutation.
The tyrosine kinase inhibitor STI571 is a promising agent for the treatment of advanced Philadelphia chromosome positive (Ph(+)) acute lymphoblastic leukemia (ALL), but resistance develops rapidly in most patients after an initial response. To identify mechanisms of resistance to STI571, 30 complementary DNAs (including 9 matched samples) obtained from the bone marrow of individuals with Ph(+) ALL were analyzed by direct sequencing of a 714-base pair region of ABL encoding for the adenosine triphosphate (ATP)-binding site and the kinase activation loop. A single point mutation was found at nucleotide 1127 (GI6382056) resulting in Glu255Lys. This mutation occurred in 6 of 9 patients (67%) following their treatment with STI571 but not in the samples from patients before beginning treatment with STI571. Glu255Lys is within the motif important for forming the pocket of the ATP-binding site in ABL and it is highly conserved across species. In conclusion, Ph(+) ALL samples resistant to STI571 have a unique mutation Glu255Lys of BCR-ABL.
Hofmann
Wolf-K
WK
Division of Hematology/Oncology, Cedars Sinai Research Institute, UCLA School of Medicine, Los Angeles, California 90048, USA. w.k.hofmann@em.uni-frankfurt.de
Jones
Letetia C
LC
Lemp
Nathan A
NA
de Vos
Sven
S
Gschaidmeier
Harald
H
Hoelzer
Dieter
D
Ottmann
Oliver G
OG
Koeffler
H Phillip
HP
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001483:Base Sequence; D001549:Benzamides; D001854:Bone Marrow Cells / Q000473:pathology; D018076:DNA, Complementary / Q000032:analysis / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D005820:Genetic Testing; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology; D008969:Molecular Sequence Data; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D017354:Point Mutation / Q000187:drug effects*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D001549:Benzamides; D018076:DNA, Complementary; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl