title: KIT signaling governs differential sensitivity of mature and primitive CML progenitors to tyrosine kinase inhibitors.
abstract: Imatinib and other BCR-ABL1 inhibitors are effective therapies for chronic myelogenous leukemia (CML), but these inhibitors target additional kinases including KIT, raising the question of whether off-target effects contribute to clinical efficacy. On the basis of its involvement in CML pathogenesis, we hypothesized that KIT may govern responses of CML cells to imatinib. To test this, we assessed the growth of primary CML progenitor cells under conditions of sole BCR-ABL1, sole KIT, and dual BCR-ABL1/KIT inhibition. Sole BCR-ABL1 inhibition suppressed mature CML progenitor cells, but these effects were largely abolished by stem cell factor (SCF) and maximal suppression required dual BCR-ABL1/KIT inhibition. In contrast, KIT inhibition did not add to the effects of BCR-ABL1 inhibition in primitive progenitors, represented by CD34(+)38(-) cells. Long-term culture-initiating cell assays on murine stroma revealed profound depletion of primitive CML cells by sole BCR-ABL1 inhibition despite the presence of SCF, suggesting that primitive CML cells are unable to use SCF as a survival factor upon BCR-ABL1 inhibition. In CD34(+)38(+) cells, SCF strongly induced pAKT(S473) in a phosphoinositide 3-kinase (PI3K)-dependent manner, which was further enhanced by inhibition of BCR-ABL1 and associated with increased colony survival. In contrast, pAKT(S473) levels remained low in CD34(+)38(-) cells cultured under the same conditions. Consistent with reduced response to SCF, KIT surface expression was significantly lower on CD34(+)38(-) compared with CD34(+)38(+) CML cells, suggesting a possible mechanism for the differential effects of SCF on mature and primitive CML progenitor cells.
authors.affiliation: Authors' Affiliations: OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Howard Hughes Medical Institute, Chevy Chase, Maryland; Huntsman Cancer Institute; Division of Hematology and Hematologic Malignancies, The University of Utah, Salt Lake City, Utah; Novartis Institutes for BioMedical Research, Basel, Switzerland; and Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Amie S
authors.initials: AS
authors.lastname: Corbin
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Hare
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Gu
authors.forename: Ira L
authors.initials: IL
authors.lastname: Kraft
authors.forename: Anna M
authors.initials: AM
authors.lastname: Eiring
authors.forename: Jamshid S
authors.initials: JS
authors.lastname: Khorashad
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Pomicter
authors.forename: Tian Y
authors.initials: TY
authors.lastname: Zhang
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Eide
authors.forename: Paul W
authors.initials: PW
authors.lastname: Manley
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Cortes
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.forename: Michael W
authors.initials: MW
authors.lastname: Deininger
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019089:Stem Cell Factor / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D018952:Antigens, CD34; D001549:Benzamides; D016044:Fusion Proteins, bcr-abl; D000068877:Imatinib Mesylate; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D019009:Proto-Oncogene Proteins c-kit; D011743:Pyrimidines; D012333:RNA, Messenger; D019089:Stem Cell Factor