Differentiation status of primary chronic myeloid leukemia cells affects sensitivity to BCR-ABL1 inhibitors

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Pietarinen , P O , Eide , C A , Ayuda-Duran , P , Potdar , S , Kuusanmaki , H , Andersson , E I , Mpindi , J P , Pemovska , T , Kontro , M , Heckman , C A , Kallioniemi , O , Wennerberg , K , Hjorth-Hansen , H , Druker , B J , Enserink , J M , Tyner , J W , Mustjoki , S & Porkka , K 2017 , ' Differentiation status of primary chronic myeloid leukemia cells affects sensitivity to BCR-ABL1 inhibitors ' , Oncotarget , vol. 8 , no. 14 , pp. 22606-22615 . https://doi.org/10.18632/oncotarget.15146

Title: Differentiation status of primary chronic myeloid leukemia cells affects sensitivity to BCR-ABL1 inhibitors
Author: Pietarinen, Paavo O.; Eide, Christopher A.; Ayuda-Duran, Pilar; Potdar, Swapnil; Kuusanmaki, Heikki; Andersson, Emma I.; Mpindi, John P.; Pemovska, Tea; Kontro, Mika; Heckman, Caroline A.; Kallioniemi, Olli; Wennerberg, Krister; Hjorth-Hansen, Henrik; Druker, Brian J.; Enserink, Jorrit M.; Tyner, Jeffrey W.; Mustjoki, Satu; Porkka, Kimmo
Contributor organization: Clinicum
University of Helsinki
Hematologian yksikkö
Department of Oncology
Department of Clinical Chemistry and Hematology
Institute for Molecular Medicine Finland
Olli-Pekka Kallioniemi / Principal Investigator
Krister Wennerberg / Principal Investigator
Department of Diagnostics and Therapeutics
HUS Comprehensive Cancer Center
Precision Systems Medicine
Date: 2017-04-04
Language: eng
Number of pages: 10
Belongs to series: Oncotarget
ISSN: 1949-2553
DOI: https://doi.org/10.18632/oncotarget.15146
URI: http://hdl.handle.net/10138/312086
Abstract: Tyrosine kinase inhibitors (TKI) are the mainstay treatment of BCR-ABL1-positive leukemia and virtually all patients with chronic myeloid leukemia in chronic phase (CP CML) respond to TKI therapy. However, there is limited information on the cellular mechanisms of response and particularly on the effect of cell differentiation state to TKI sensitivity in vivo and ex vivo/in vitro. We used multiple, independent high-throughput drug sensitivity and resistance testing platforms that collectively evaluated 295 oncology compounds to characterize ex vivo drug response profiles of primary cells freshly collected from newly-diagnosed patients with BCR-ABL1positive leukemia (n = 40) and healthy controls (n = 12). In contrast to the highly TKI-sensitive cells from blast phase CML and Philadelphia chromosome-positive acute lymphoblastic leukemia, primary CP CML cells were insensitive to TKI therapy ex vivo. Despite maintaining potent BCR-ABL1 inhibitory activity, ex vivo viability of cells was unaffected by TKIs. These findings were validated in two independent patient cohorts and analysis platforms. All CP CML patients under study responded to TKI therapy in vivo. When CP CML cells were sorted based on CD34 expression, the CD34-positive progenitor cells showed good sensitivity to TKIs, whereas the more mature CD34-negative cells were markedly less sensitive. Thus in CP CML, TKIs predominantly target the progenitor cell population while the differentiated leukemic cells (mostly cells from granulocytic series) are insensitive to BCR-ABL1 inhibition. These findings have implications for drug discovery in CP CML and indicate a fundamental biological difference between CP CML and advanced forms of BCR-ABL1-positive leukemia.
Subject: chronic myeloid leukemia
high-throughput drug screening
ex vivo
tyrosine kinase inhibitors
3122 Cancers
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion

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