title: Targeting primitive chronic myeloid leukemia cells by effective inhibition of a new AHI-1-BCR-ABL-JAK2 complex.
abstract: BACKGROUND
  Imatinib mesylate (IM) induces clinical remission of chronic myeloid leukemia (CML). The Abelson helper integration site 1 (AHI-1) oncoprotein interacts with BCR-ABL and Janus kinase 2 (JAK2) to mediate IM response of primitive CML cells, but the effect of the interaction complex on the response to ABL and JAK2 inhibitors is unknown.
  
  
  METHODS
  The AHI-1-BCR-ABL-JAK2 interaction complex was analyzed by mutational analysis and coimmunoprecipitation. Roles of the complex in regulation of response or resistance to ABL and JAK2 inhibitors were investigated in BCR-ABL (+) cells and primary CML stem/progenitor cells and in immunodeficient NSG mice. All statistical tests were two-sided.
  
  
  RESULTS
  The WD40-repeat domain of AHI-1 interacts with BCR-ABL, whereas the N-terminal region interacts with JAK2; loss of these interactions statistically significantly increased the IM sensitivity of CML cells. Disrupting this complex with a combination of IM and an orally bioavailable selective JAK2 inhibitor (TG101209 [TG]) statistically significantly induced death of AHI-1-overexpressing and IM-resistant cells in vitro and enhanced survival of leukemic mice, compared with single agents (combination vs TG alone: 63 vs 53 days, ratio = 0.84, 95% confidence interval [CI] = 0.6 to 1.1, P = .004; vs IM: 57 days, ratio = 0.9, 95% CI = 0.61 to 1.2, P = .003). Combination treatment also statistically significantly enhanced apoptosis of CD34(+) leukemic stem/progenitor cells and eliminated their long-term leukemia-initiating activity in NSG mice. Importantly, this approach was effective against treatment-naive CML stem cells from patients who subsequently proved to be resistant to IM therapy.
  
  
  CONCLUSIONS
  Simultaneously targeting BCR-ABL and JAK2 activities in CML stem/progenitor cells may improve outcomes in patients destined to develop IM resistance.
authors: Terry Fox Laboratory, BC Cancer Agency, 675 W 10th Ave, Vancouver, BC, V5Z 1L3, Canada.
authors: Min
authors: M
authors: Chen
authors: Paolo
authors: P
authors: Gallipoli
authors: Donna
authors: D
authors: DeGeer
authors: Ivan
authors: I
authors: Sloma
authors: Donna L
authors: DL
authors: Forrest
authors: Matthew
authors: M
authors: Chan
authors: Damian
authors: D
authors: Lai
authors: Heather
authors: H
authors: Jorgensen
authors: Ashley
authors: A
authors: Ringrose
authors: Hui Mi
authors: HM
authors: Wang
authors: Karen
authors: K
authors: Lambie
authors: Helen
authors: H
authors: Nakamoto
authors: Kyi Min
authors: KM
authors: Saw
authors: Ali
authors: A
authors: Turhan
authors: Ralph
authors: R
authors: Arlinghaus
authors: James
authors: J
authors: Paul
authors: Jon
authors: J
authors: Stobo
authors: Michael J
authors: MJ
authors: Barnett
authors: Allen
authors: A
authors: Eaves
authors: Connie J
authors: CJ
authors: Eaves
authors: Tessa L
authors: TL
authors: Holyoake
authors: Xiaoyan
authors: X
authors: Jiang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D033942:Adaptor Proteins, Vesicular Transport; D000284:Administration, Oral; D000818:Animals; D018952:Antigens, CD34 / Q000032:analysis; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D001682:Biological Availability; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D004252:DNA Mutational Analysis; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000068877:Imatinib Mesylate; D047468:Immunoprecipitation; D053614:Janus Kinase 2 / Q000378:metabolism*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism*; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism*; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D012074:Remission Induction; D013449:Sulfonamides / Q000494:pharmacology; D015854:Up-Regulation; D000096926:Benzenesulfonamides
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D018952:Antigens, CD34; D001549:Benzamides; D016044:Fusion Proteins, bcr-abl; D000068877:Imatinib Mesylate; D053614:Janus Kinase 2; D008840:Microfilament Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; C487178:AHI1 protein, human; C522865:TG101209; D000096926:Benzenesulfonamides; C118067:WDR1 protein, human; C507924:JAK2 protein, human