Modeling the influence of stromal microenvironment in the selection of ENU-induced BCR-ABL1 mutants by tyrosine kinase inhibitors

Abstract

Tyrosine kinase inhibitors (TKIs) have profoundly changed the natural history of chronic myeloid leukemia (CML). However, acquired resistance to imatinib, dasatinib or nilotinib (1st and 2nd generation TKIs), due in part to BCR-ABL1 kinase mutations, has been largely described. These drugs are ineffective on the T315I gatekeeper substitution, which remains sensitive to 3rd generation TKI ponatinib. 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, ENU (N-ethyl-N-nitrosourea)-exposed UT-7 cells expressing non-mutated or T315I-mutated BCR-ABL1 were cultured with or without murine MS-5 stromal cells and in the presence of imatinib, dasatinib, nilotinib, or ponatinib. In the assays relative to 1st and 2nd 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 ponatinib assays performed on both non-mutated and T315I–mutated BCR-ABL1 cells, an increased number of resistant clones were observed in the presence of MS-5. Present data suggested that T315I mutants need either compound mutations (e.g. E255K/T315I) or a stromal niche to escape from ponatinib. 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 ponatinib, by providing survival signals and favoring genetic instability.

PIG7 promotes leukemia cell chemosensitivity via lysosomal membrane permeabilization

“…For many years, caspases have been taken as the major class of proteases involved in the execution of cellular apoptosis [ 37 – 40 ]. There are a number of publications suggesting that caspases—under certain circumstances—are involved in the lysosomal release of apoptogenic factors [ 34 , 41 – 46 ]. In our study, we found that the overexpression of pig7 alone could not activate caspase 9/Apaf-1 complex and caspase-3.…”

The stromal genome heterogeneity between breast and prostate tumors revealed by a comparative transcriptomic analysis

“…One important reason why gene expression of cancer stroma has potential for cancer treatment and prediction is that cancer stroma maintains a normal genotype, because stromal reactions in response to cancer epithelium mostly only alter gene expression, without drastic and stochastic genomic changes [ 15 , 16 ]. In addition, due to coevolution of cancer and stroma in the process of cancer progression, many genes were commonly expressed in stroma and cancer cells [ 17 ].…”

Latest progress in tyrosine kinase inhibitors

“…Also, hematopoietic niche could protect leukemic cells from therapy [21]. Aggoune et al demonstrated that T315I mutants need either compound mutations such as E255K/T315I or a stromal niche to escape from the toxicity of ponatinib [21].…”

“…Also, hematopoietic niche could protect leukemic cells from therapy [21]. Aggoune et al demonstrated that T315I mutants need either compound mutations such as E255K/T315I or a stromal niche to escape from the toxicity of ponatinib [21]. Thus the hematopoietic niche plays a crucial role in conferring resistance to ponatinib, by increasing cell survival and genetic instability [21].…”

“…Aggoune et al demonstrated that T315I mutants need either compound mutations such as E255K/T315I or a stromal niche to escape from the toxicity of ponatinib [21]. Thus the hematopoietic niche plays a crucial role in conferring resistance to ponatinib, by increasing cell survival and genetic instability [21]. This is especially striking given that chronic myelogenous cells that are resistant to all kinase inhibitors are still highly sensitive to ponatinib [22, 23].…”