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Genes Chromosomes Cancer. 2010 Oct;49(10):910-8. doi: 10.1002/gcc.20801.

Associations between imatinib resistance conferring mutations and Philadelphia positive clonal cytogenetic evolution in CML.

Author information

1
MLL Munich Leukemia Laboratory GmbH, Munich, Germany. susanne.schnittger@mll-online.com

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.

PMID:
20607847
DOI:
10.1002/gcc.20801
[Indexed for MEDLINE]

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