BCR-ABL mutants spread resistance to non-mutated cells through a paracrine mechanism

Abstract

Patients with chronic myeloid leukemia who become resistant to the Abl kinase inhibitor imatinib can be treated with dasatinib. This sequential treatment can lead to BCR-ABL mutations conferring broad resistance to kinase inhibitors. To model the evolution of resistance, we exposed the mouse DA1-3b BCR-ABL+ leukemic cell line to imatinib for several months, and obtained resistant cells carrying the E255K mutation. We then exposed these cells to dasatinib, and obtained dasatinib-resistant cells with composite E255K+T315I mutations. Subcloning isolated a minor clone also carrying V299L. In co-culture, mutated cells were able to spread resistance to non-mutated cells through overexpression of interleukin 3, activation of MEK/ERK and JAK2/STAT5 pathways, and downregulation of Bim. Even the presence of less than 10% of mutated cells was sufficient to protect non-mutated cells. Blocking JAK2 and MEK1/2 inhibited the protective effect of co-culture. Mutated cells were also sensitive to JAK2 inhibition, but blocking MEK1/2 alone, or in association with kinase inhibitors, had little effect. These data indicate that sequential Abl kinase inhibitor therapy can generate sub-populations of mutated cells, which may coexist with non-mutated cells and protect them through a paracrine mechanism. Targeting JAK2 could eliminate both populations.

DOI: 10.1038/leu.2008.3

Statistics

02004002008200920102011201220132014201520162017
Citations per Year

709 Citations

Semantic Scholar estimates that this publication has 709 citations based on the available data.

See our FAQ for additional information.

Cite this paper

@article{Liu2008BCRABLMS, title={BCR-ABL mutants spread resistance to non-mutated cells through a paracrine mechanism}, author={Juliet Juan Liu and Sami Joha and Thierry Idziorek and S{\'e}lim Corm and Dominique H{\'e}tuin and No{\"{e}l Philippe and Claude Joseph Preudhomme and Bruno Quesnel}, journal={Leukemia}, year={2008}, volume={22}, pages={791-799} }