shRNA library screening identifies nucleocytoplasmic transport as a mediator of BCR-ABL1 kinase-independent resistance.

Autor:	Khorashad JS; Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT;, Eiring AM; Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT;, Mason CC; Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT;, Gantz KC; Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT;, Bowler AD; Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT;, Redwine HM; Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT;, Yu F; Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT; Beijing Tsinghua Chang Gung Hospital, Tsinghua University, Beijing, China;, Kraft IL; Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT;, Pomicter AD; Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT;, Reynolds KR; Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT;, Iovino AJ; Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT;, Zabriskie MS; Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT;, Heaton WL; Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT;, Tantravahi SK; Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT; Division of Hematology and Hematologic Malignancies, The University of Utah, Salt Lake City, UT;, Kauffman M; Karyopharm Therapeutics, Natick, MA; and., Shacham S; Karyopharm Therapeutics, Natick, MA; and., Chenchik A; Cellecta, Mountain View, CA., Bonneau K; Cellecta, Mountain View, CA., Ullman KS; Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT;, O'Hare T; Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT; Division of Hematology and Hematologic Malignancies, The University of Utah, Salt Lake City, UT;, Deininger MW; Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT; Division of Hematology and Hematologic Malignancies, The University of Utah, Salt Lake City, UT;
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2015 Mar 12; Vol. 125 (11), pp. 1772-81. Date of Electronic Publication: 2015 Jan 08.
DOI:	10.1182/blood-2014-08-588855
Abstrakt:	The mechanisms underlying tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia (CML) patients lacking explanatory BCR-ABL1 kinase domain mutations are incompletely understood. To identify mechanisms of TKI resistance that are independent of BCR-ABL1 kinase activity, we introduced a lentiviral short hairpin RNA (shRNA) library targeting ∼5000 cell signaling genes into K562(R), a CML cell line with BCR-ABL1 kinase-independent TKI resistance expressing exclusively native BCR-ABL1. A customized algorithm identified genes whose shRNA-mediated knockdown markedly impaired growth of K562(R) cells compared with TKI-sensitive controls. Among the top candidates were 2 components of the nucleocytoplasmic transport complex, RAN and XPO1 (CRM1). shRNA-mediated RAN inhibition or treatment of cells with the XPO1 inhibitor, KPT-330 (Selinexor), increased the imatinib sensitivity of CML cell lines with kinase-independent TKI resistance. Inhibition of either RAN or XPO1 impaired colony formation of CD34(+) cells from newly diagnosed and TKI-resistant CML patients in the presence of imatinib, without effects on CD34(+) cells from normal cord blood or from a patient harboring the BCR-ABL1(T315I) mutant. These data implicate RAN in BCR-ABL1 kinase-independent imatinib resistance and show that shRNA library screens are useful to identify alternative pathways critical to drug resistance in CML. (© 2015 by The American Society of Hematology.)
Databáze:	MEDLINE
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