title: Differentiation status of primary chronic myeloid leukemia cells affects sensitivity to BCR-ABL1 inhibitors.
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-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.
authors.affiliation: Hematology Research Unit Helsinki, University of Helsinki and Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
authors.forename: Paavo O
authors.initials: PO
authors.lastname: Pietarinen
authors.affiliation: Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.|Howard Hughes Medical Institute, Portland, OR, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Eide
authors.affiliation: Oslo University Hospital, University of Oslo, Oslo, Norway.
authors.forename: Pilar
authors.initials: P
authors.lastname: Ayuda-Durán
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors.forename: Swapnil
authors.initials: S
authors.lastname: Potdar
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors.forename: Heikki
authors.initials: H
authors.lastname: Kuusanmäki
authors.affiliation: Hematology Research Unit Helsinki, University of Helsinki and Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
authors.forename: Emma I
authors.initials: EI
authors.lastname: Andersson
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors.forename: John P
authors.initials: JP
authors.lastname: Mpindi
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.|Research Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Tea
authors.initials: T
authors.lastname: Pemovska
authors.affiliation: Hematology Research Unit Helsinki, University of Helsinki and Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
authors.forename: Mika
authors.initials: M
authors.lastname: Kontro
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Heckman
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Kallioniemi
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors.forename: Krister
authors.initials: K
authors.lastname: Wennerberg
authors.affiliation: Department of Hematology, St Olavs Hospital, Trondheim, Norway and Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
authors.forename: Henrik
authors.initials: H
authors.lastname: Hjorth-Hansen
authors.affiliation: Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.|Howard Hughes Medical Institute, Portland, OR, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.affiliation: Oslo University Hospital, University of Oslo, Oslo, Norway.
authors.forename: Jorrit M
authors.initials: JM
authors.lastname: Enserink
authors.affiliation: Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.|Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Tyner
authors.affiliation: Hematology Research Unit Helsinki, University of Helsinki and Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.|Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland.
authors.forename: Satu
authors.initials: S
authors.lastname: Mustjoki
authors.affiliation: Hematology Research Unit Helsinki, University of Helsinki and Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
authors.forename: Kimmo
authors.initials: K
authors.lastname: Porkka
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D015331:Cohort Studies; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000145:classification / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D016044:Fusion Proteins, bcr-abl
keywords: CD34; chronic myeloid leukemia; ex vivo; high-throughput drug screening; tyrosine kinase inhibitors