SNP array analysis of tyrosine kinase inhibitor-resistant chronic myeloid leukemia identifies heterogeneous secondary genomic alterations.

Abstract

To elucidate whether tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia is associated with characteristic genomic alterations, we analyzed DNA samples from 45 TKI-resistant chronic myeloid leukemia patients with 250K single nucleotide polymorphism arrays. From 20 patients, matched serial samples of pretreatment and TKI resistance time points were available. Eleven of the 45 TKI-resistant patients had mutations of BCR-ABL1, including 2 T315I mutations. Besides known TKI resistance-associated genomic lesions, such as duplication of the BCR-ABL1 gene (n = 8) and trisomy 8 (n = 3), recurrent submicroscopic alterations, including acquired uniparental disomy, were detectable on chromosomes 1, 8, 9, 17, 19, and 22. On chromosome 22, newly acquired and recurrent deletions of the IGLC1 locus were detected in 3 patients, who had previously presented with lymphoid or myeloid blast crisis. This may support a hypothesis of TKI-induced selection of subclones differentiating into immature B-cell progenitors as a mechanism of disease progression and evasion of TKI sensitivity.

• Authors: Daniel Nowak, Seishi Ogawa, Markus Müschen, Motohiro Kato, Norihiko Kawamata, Antonie Meixel, Verena Nowak, Han S Kim, Sharon Kang, Ronald Paquette, Mi-Sook Chang, Nils H Thoennissen, Nils H Thoenissen, Max Mossner, Wolf-Karsten Hofmann, Alexander Kohlmann, Tamara Weiss, Torsten Haferlach, Claudia Haferlach, H Phillip Koeffler
• Journal: Blood (Blood) Vol. 115 Issue 5 Pg. 1049-53 (Feb 04 2010) ISSN: 1528-0020 [Electronic] United States
• PMID: 19965645 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Benzamides
• Piperazines
• Protein Kinase Inhibitors
• Pyrimidines
• Thiazoles
• Imatinib Mesylate
• Protein-Tyrosine Kinases
• Fusion Proteins, bcr-abl
• nilotinib
• Dasatinib

Topics

• Benzamides
• Chromosome Aberrations
• Chromosomes, Human, Pair 1 (genetics)
• Chromosomes, Human, Pair 17 (genetics)
• Chromosomes, Human, Pair 19 (genetics)
• Chromosomes, Human, Pair 22 (genetics)
• Chromosomes, Human, Pair 8 (genetics)
• Chromosomes, Human, Pair 9 (genetics)
• Dasatinib
• Drug Resistance, Neoplasm (genetics)
• Fusion Proteins, bcr-abl (genetics)
• Gene Expression Profiling
• Gene Expression Regulation, Leukemic
• Humans
• Imatinib Mesylate
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, genetics)
• Mutation
• Oligonucleotide Array Sequence Analysis (methods)
• Piperazines (pharmacology, therapeutic use)
• Polymorphism, Single Nucleotide
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Protein-Tyrosine Kinases (antagonists & inhibitors, genetics)
• Pyrimidines (pharmacology, therapeutic use)
• Thiazoles (pharmacology, therapeutic use)