title: Ph(+) acute lymphoblastic leukemia resistant to the tyrosine kinase inhibitor STI571 has a unique BCR-ABL gene mutation.
abstract: 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.
authors.affiliation: Division of Hematology/Oncology, Cedars Sinai Research Institute, UCLA School of Medicine, Los Angeles, California 90048, USA. w.k.hofmann@em.uni-frankfurt.de
authors.forename: Wolf-K
authors.initials: WK
authors.lastname: Hofmann
authors.forename: Letetia C
authors.initials: LC
authors.lastname: Jones
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Lemp
authors.forename: Sven
authors.initials: S
authors.lastname: de Vos
authors.forename: Harald
authors.initials: H
authors.lastname: Gschaidmeier
authors.forename: Dieter
authors.initials: D
authors.lastname: Hoelzer
authors.forename: Oliver G
authors.initials: OG
authors.lastname: Ottmann
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
mesh_terms: 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*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D018076:DNA, Complementary; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl