Modeling the influence of stromal microenvironment in the selection of XXXX -induced BCR-ABL1 mutants by @entity669 kinase inhibitors.

@entity1 @entity8947 @entity34679 @entity330 @entity19 @entity28837 @entity331 @entity669 @entity1860 @entity28833 @entity10542 @entity2213
@entity669 kinase inhibitors (TKIs) have profoundly changed the natural history of @entity1860 ( @entity1860 ). However, acquired resistance to @entity2213 , @entity8947 or @entity10542 (1(st) and 2(nd) generation TKIs), due in part to BCR-ABL1 kinase mutations, has been largely described. These drugs are ineffective on the @entity28837 gatekeeper substitution, which remains sensitive to 3(rd) generation TKI @entity34679 . It has recently been suggested that the hematopoietic niche could protect leukemic cells from targeted therapy. In order to investigate the role of a stromal niche in mutation-related resistance, we developed a niche-based cell mutagenesis assay. For this purpose, @entity331 ( @entity330 )-exposed @entity1 cells expressing non-mutated or @entity28837 -mutated BCR-ABL1 were cultured with or without @entity19 @entity19 stromal cells and in the presence of @entity2213 , @entity8947 , @entity10542 , or @entity34679 . In the assays relative to 1(st) and 2(nd) generation TKIs, which were performed on non-mutated BCR-ABL1 cells, our data highlighted the increasing efficacy of the latter, but did not reveal any substantial effect of the niche. In @entity34679 assays performed on both non-mutated and @entity28837 -mutated BCR-ABL1 cells, an increased number of resistant clones were observed in the presence of MS-5. Present data suggested that @entity28837 mutants need either compound mutations (e.g. @entity28833 / @entity28837 ) or a stromal niche to escape from @entity34679 . Using array-comparative genomic hybridization experiments, we found an increased number of variations (involving some recurrent chromosome regions) in clones cultured on MS-5 feeder. Overall, our study suggests that the hematopoietic niche could play a crucial role in conferring resistance to @entity34679 , by providing survival signals and favoring genetic instability.
