title: Efficacy of Retinoids in IKZF1-Mutated BCR-ABL1 Acute Lymphoblastic Leukemia.
abstract: Alterations of IKZF1, encoding the lymphoid transcription factor IKAROS, are a hallmark of high-risk acute lymphoblastic leukemia (ALL), however the role of IKZF1 alterations in ALL pathogenesis is poorly understood. Here, we show that in mouse models of BCR-ABL1 leukemia, Ikzf1 and Arf alterations synergistically promote the development of an aggressive lymphoid leukemia. Ikzf1 alterations result in acquisition of stem cell-like features, including self-renewal and increased bone marrow stromal adhesion. Retinoid receptor agonists reversed this phenotype, partly by inducing expression of IKZF1, resulting in abrogation of adhesion and self-renewal, cell cycle arrest, and attenuation of proliferation without direct cytotoxicity. Retinoids potentiated the activity of dasatinib in mouse and human BCR-ABL1 ALL, providing an additional therapeutic option in IKZF1-mutated ALL.
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Michelle L
authors: ML
authors: Churchman
authors: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Jonathan
authors: J
authors: Low
authors: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Chunxu
authors: C
authors: Qu
authors: Department of Medicine, Montefiore Medical Center, North Division, Bronx, NY 10466, USA.
authors: Elisabeth M
authors: EM
authors: Paietta
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Lawryn H
authors: LH
authors: Kasper
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Yunchao
authors: Y
authors: Chang
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Debbie
authors: D
authors: Payne-Turner
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Mark J
authors: MJ
authors: Althoff
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Guangchun
authors: G
authors: Song
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Shann-Ching
authors: SC
authors: Chen
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Jing
authors: J
authors: Ma
authors: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Michael
authors: M
authors: Rusch
authors: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Dan
authors: D
authors: McGoldrick
authors: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Michael
authors: M
authors: Edmonson
authors: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Pankaj
authors: P
authors: Gupta
authors: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Yong-Dong
authors: YD
authors: Wang
authors: Preclinical Pharmacokinetics Shared Resource, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: William
authors: W
authors: Caufield
authors: Preclinical Pharmacokinetics Shared Resource, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Burgess
authors: B
authors: Freeman
authors: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Lie
authors: L
authors: Li
authors: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: John C
authors: JC
authors: Panetta
authors: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Sharyn
authors: S
authors: Baker
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Yung-Li
authors: YL
authors: Yang
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Kathryn G
authors: KG
authors: Roberts
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Kelly
authors: K
authors: McCastlain
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Ilaria
authors: I
authors: Iacobucci
authors: Department of Cellular Imaging Shared Resource, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Jennifer L
authors: JL
authors: Peters
authors: Department of Cellular Imaging Shared Resource, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Victoria E
authors: VE
authors: Centonze
authors: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors: Faiyaz
authors: F
authors: Notta
authors: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors: Stephanie M
authors: SM
authors: Dobson
authors: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors: Sasan
authors: S
authors: Zandi
authors: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors: John E
authors: JE
authors: Dick
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Laura
authors: L
authors: Janke
authors: Departments of Structural Biology and Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; St. Jude Proteomics Facility, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Junmin
authors: J
authors: Peng
authors: St. Jude Proteomics Facility, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Kiran
authors: K
authors: Kodali
authors: St. Jude Proteomics Facility, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Vishwajeeth
authors: V
authors: Pagala
authors: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Jaeki
authors: J
authors: Min
authors: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Anand
authors: A
authors: Mayasundari
authors: Puma Biotechnology, Los Angeles, CA 90024, USA.
authors: Richard T
authors: RT
authors: Williams
authors: Department of Pathology, University of New Mexico Cancer Center, Albuquerque, NM 87131, USA.
authors: Cheryl L
authors: CL
authors: Willman
authors: Hematology, Shaare Zedek Medical Center, 9103102 Jerusalem, Israel.
authors: Jacob
authors: J
authors: Rowe
authors: Hematology-Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Selina
authors: S
authors: Luger
authors: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
authors: Ross A
authors: RA
authors: Dickins
authors: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: R Kiplin
authors: RK
authors: Guy
authors: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Taosheng
authors: T
authors: Chen
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: charles.mullighan@stjude.org.
authors: Charles G
authors: CG
authors: Mullighan
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics*; D051379:Mice; D009154:Mutation / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D012176:Retinoids / Q000378:metabolism*
chemical_list: D018168:Receptors, Retinoic Acid; D012176:Retinoids; D051740:Ikaros Transcription Factor; D016044:Fusion Proteins, bcr-abl