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Associations between imatinib resistance conferring mutations and Philadelphia positive clonal cytogenetic evolution in CML
Author(s) -
Schnittger Susanne,
Bacher Ulrike,
Dicker Frank,
Kern Wolfgang,
Alpermann Tamara,
Haferlach Torsten,
Haferlach Claudia
Publication year - 2010
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/gcc.20801
Subject(s) - imatinib , mutation , philadelphia chromosome , myeloid leukemia , biology , cytogenetics , abl , genetics , protein kinase domain , cancer research , chromosomal translocation , microbiology and biotechnology , chromosome , medicine , gene , tyrosine kinase , mutant , receptor
Abstract In patients with chronic myeloid leukemia (CML), resistance against imatinib is associated with mutations in the kinase domain (KD) of the BCR‐ABL1 fusion gene and/or with additional chromosomal abnormalities (ACAs) secondary to the Philadelphia chromosome. To evaluate associations between these molecular and cytogenetic events, we correlated cytogenetic data with results of KD mutation analysis in 205 CML patients with acquired resistance to imatinib (100 females, 105 males, 17.9‐90.3 years). In 79/205 patients (38.5%), at least one KD mutation was detected; in 13/79 (16.5%) even two different mutations were observed. A second KD mutation was frequent in cases with G250E (4/9), E255V (1/3), T315I (5/18), F317L (2/7), F359C/V (4/7), or H396R (2/3), but was never detected in cases with V299L ( n = 3) or Y253H ( n = 4). With respect to cytogenetics, ACAs were identified in 76/205 patients (37.1%), in 29 (36.7%) together with KD mutations. ACAs were frequent in cases with E255V (2/3), T315I (8/18), F317L (4/7), F359C/V (4/7), or H396R (2/3), but rare in those with M351T (1/9). Therefore, some KD mutations (e.g., T315I) might be associated with higher genetic instability paving the way to additional cytogenetic and molecular genetic events. © 2010 Wiley‐Liss, Inc.