TY - JOUR

T1 - Differentiation status of primary chronic myeloid leukemia cells affects sensitivity to BCR-ABL1 inhibitors

AU - Pietarinen, Paavo O

AU - Eide, Christopher A

AU - Ayuda-Durán, Pilar

AU - Potdar, Swapnil

AU - Kuusanmäki, Heikki

AU - Andersson, Emma I

AU - Mpindi, John P

AU - Pemovska, Tea

AU - Kontro, Mika

AU - Heckman, Caroline A

AU - Kallioniemi, Olli

AU - Wennerberg, Krister

AU - Hjorth-Hansen, Henrik

AU - Druker, Brian J

AU - Enserink, Jorrit M

AU - Tyner, Jeffrey W

AU - Mustjoki, Satu

AU - Porkka, Kimmo

PY - 2017/4/4

Y1 - 2017/4/4

N2 - 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-ABL1-positive 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.

AB - 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-ABL1-positive 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.

KW - Apoptosis/drug effects

KW - Biomarkers, Tumor/metabolism

KW - Cell Differentiation/drug effects

KW - Cell Proliferation/drug effects

KW - Cohort Studies

KW - Drug Resistance, Neoplasm/drug effects

KW - Fusion Proteins, bcr-abl/metabolism

KW - High-Throughput Screening Assays/methods

KW - Humans

KW - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/classification

KW - Protein Kinase Inhibitors/pharmacology

KW - Tumor Cells, Cultured

U2 - 10.18632/oncotarget.15146

DO - 10.18632/oncotarget.15146

M3 - Journal article

C2 - 28186983

VL - 8

SP - 22606

EP - 22615

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 14

ER -