title: Disruption of IKAROS activity in primitive chronic-phase CML cells mimics myeloid disease progression.
abstract: Without effective therapy, chronic-phase chronic myeloid leukemia (CP-CML) evolves into an acute leukemia (blast crisis [BC]) that displays either myeloid or B-lymphoid characteristics. This transition is often preceded by a clinically recognized, but biologically poorly characterized, accelerated phase (AP). Here, we report that IKAROS protein is absent or reduced in bone marrow blasts from most CML patients with advanced myeloid disease (AP or BC). This contrasts with primitive CP-CML cells and BCR-ABL1-negative acute myeloid leukemia blasts, which express readily detectable IKAROS. To investigate whether loss of IKAROS contributes to myeloid disease progression in CP-CML, we examined the effects of forced expression of a dominant-negative isoform of IKAROS (IK6) in CP-CML patients' CD34(+) cells. We confirmed that IK6 disrupts IKAROS activity in transduced CP-CML cells and showed that it confers on them features of AP-CML, including a prolonged increased output in vitro and in xenografted mice of primitive cells with an enhanced ability to differentiate into basophils. Expression of IK6 in CD34(+) CP-CML cells also led to activation of signal transducer and activator of transcription 5 and transcriptional repression of its negative regulators. These findings implicate loss of IKAROS as a frequent step and potential diagnostic harbinger of progressive myeloid disease in CML patients.
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency and University of British Columbia, Vancouver, BC, Canada;
authors.forename: Philip A
authors.initials: PA
authors.lastname: Beer
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency and University of British Columbia, Vancouver, BC, Canada;
authors.forename: David J H F
authors.initials: DJ
authors.lastname: Knapp
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency and University of British Columbia, Vancouver, BC, Canada;
authors.forename: Paul H
authors.initials: PH
authors.lastname: Miller
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency and University of British Columbia, Vancouver, BC, Canada;
authors.forename: Nagarajan
authors.initials: N
authors.lastname: Kannan
authors.affiliation: Laboratoire d'Hématologie, Hôpital Paul Brousse, Assistance Publique des Hôpitaux de Paris, INSERM U935, Villejuif, France;
authors.forename: Ivan
authors.initials: I
authors.lastname: Sloma
authors.affiliation: School of Pathology and Laboratory Medicine, The University of Western Australia, Crawley WA, Australia;
authors.forename: Kathy
authors.initials: K
authors.lastname: Heel
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency and University of British Columbia, Vancouver, BC, Canada;
authors.forename: Sonja
authors.initials: S
authors.lastname: Babovic
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency and University of British Columbia, Vancouver, BC, Canada;
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Bulaeva
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency and University of British Columbia, Vancouver, BC, Canada;
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Rabu
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University Medical Centre, Hamilton, ON, Canada;
authors.forename: Jefferson
authors.initials: J
authors.lastname: Terry
authors.affiliation: Knight Cancer Institute, Oregon Health & Science University, Portland, OR; and.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.affiliation: Knight Cancer Institute, Oregon Health & Science University, Portland, OR; and.
authors.forename: Marc M
authors.initials: MM
authors.lastname: Loriaux
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Keith R
authors.initials: KR
authors.lastname: Loeb
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Jerald P
authors.initials: JP
authors.lastname: Radich
authors.affiliation: School of Pathology and Laboratory Medicine, The University of Western Australia, Crawley WA, Australia;
authors.forename: Wendy N
authors.initials: WN
authors.lastname: Erber
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency and University of British Columbia, Vancouver, BC, Canada;
authors.forename: Connie J
authors.initials: CJ
authors.lastname: Eaves
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001491:Basophils / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018450:Disease Progression; D004804:Eosinophils / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D005434:Flow Cytometry; D006801:Humans; D051740:Ikaros Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D007124:Immunoenzyme Techniques; D015466:Leukemia, Myeloid, Chronic-Phase / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D018952:Antigens, CD34; C586512:Ikaros 6 protein, human; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D050799:STAT5 Transcription Factor; D051740:Ikaros Transcription Factor; D011505:Protein-Tyrosine Kinases