Tyrosine kinase inhibitors (TKIs) elicit high response rates among individuals with kinase-driven malignancies, including chronic myeloid leukemia (CML) and epidermal growth factor receptor-mutated non-small-cell lung cancer (EGFR NSCLC). However, the extent and duration of these responses are heterogeneous, suggesting the existence of genetic modifiers affecting an individual's response to TKIs. Using paired-end DNA sequencing, we discovered a common intronic deletion polymorphism in the gene encoding BCL2-like 11 (BIM). BIM is a pro-apoptotic member of the B-cell CLL/lymphoma 2 (BCL2) family of proteins, and its upregulation is required for TKIs to induce apoptosis in kinase-driven cancers. The polymorphism switched BIM splicing from exon 4 to exon 3, which resulted in expression of BIM isoforms lacking the pro-apoptotic BCL2-homology domain 3 (BH3). The polymorphism was sufficient to confer intrinsic TKI resistance in CML and EGFR NSCLC cell lines, but this resistance could be overcome with BH3-mimetic drugs. Notably, individuals with CML and EGFR NSCLC harboring the polymorphism experienced significantly inferior responses to TKIs than did individuals without the polymorphism (P = 0.02 for CML and P = 0.027 for EGFR NSCLC). Our results offer an explanation for the heterogeneity of TKI responses across individuals and suggest the possibility of personalizing therapy with BH3 mimetics to overcome BIM-polymorphism-associated TKI resistance.

We have cloned and sequenced the teleost homoiogs of the human genes encoding platelet-derived growth factor receptor-13 (PDGFRI3) and macrophage colony-stimulating factor I receptor (CSF1R) from the puffer fish Fugu rubripes. The Fugu PDGFRI3 and CSFIR genes each consist of 21 coding exons similar to the human CSFIR gene, but are considerably smaller than their human counterparts because of the smaller introns. Furthermore, the two Fugu genes are linked tandemly in a head-to-tail array similar to their human homologs with 2.2 kb of intergenic sequence. Amino acid sequences of the Fugu and human PDGFRI3 and CSFIR genes show an overall homology of 45% and 39%, respectively, with the kinase domains showing a much higher degree of conservation. Dot-matrix analysis revealed several short stretches of conserved sequences in the 3' untranslated regions of the PDGFRI3 genes and the adjacent promoter regions of the CSFIR genes. These conserved sequences may have a role in the regulation of expression of either or both of these closely linked genes.[The sequence data described in this paper have been submitted to GenBank under accession no. U63926.]The Japanese puffer fish Fugu rubripes has a small genome of 390 Mb which is -8 times smaller than the mammalian genomes (Brenner et al. 1993). Because teleosts have a body plan similar to that of mammals and possess most of their complex physiological functions, it is not surprising that the Fugu genome has a gene repertoire comparable to that of mammals (Brenner et al. 1993).This implies that the gene density in the Fugu genome is higher than in mammalian genomes.The compact genome of Fugu with small introns and a low abundance of repetitive elements (Brenner et

No abstract

No abstract