An East-Asian polymorphism underlies BCR-ABL mutation-independent resistance to tyrosine kinase inhibitors in chronic myelogenous leukemia

ABSTRACT: We used massively parallel DNA sequencing of paired-end ditags (DNA-PET) to identify structural genetic factors associated with disease progression and drug-resistance in representative samples from four CML patients and one CML cell line. The functional consequences of our genetic findings were evaluated in primary CML cells and cell lines, and validated in a larger CML cohort. We discovered a novel intronic deletion that correlated with imatinib-resistance, and was subsequently confirmed to be a polymorphism in normal East-Asian, but not African or Caucasian, populations. We found that the polymorphism favored expression of transcripts lacking a pro-apoptotic domain, which is critical for imatinib-induced cell death. A CML cell line containing the polymorphism also exhibited BCR-ABL-independent imatinib-resistance. Structural variations of 5 human CML samples were identified by long span paired-end sequencing

ORGANISM(S): Homo sapiens

SUBMITTER: Axel HILLMER 

PROVIDER: E-GEOD-28303 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress