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Cancer Cell. 2015 Sep 14;28(3):343-56. doi: 10.1016/j.ccell.2015.07.016. Epub 2015 Aug 27.

Efficacy of Retinoids in IKZF1-Mutated BCR-ABL1 Acute Lymphoblastic Leukemia.

Author information

1
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
2
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
3
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
4
Department of Medicine, Montefiore Medical Center, North Division, Bronx, NY 10466, USA.
5
Preclinical Pharmacokinetics Shared Resource, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
6
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
7
Department of Cellular Imaging Shared Resource, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
8
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada.
9
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.
10
St. Jude Proteomics Facility, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
11
Puma Biotechnology, Los Angeles, CA 90024, USA.
12
Department of Pathology, University of New Mexico Cancer Center, Albuquerque, NM 87131, USA.
13
Hematology, Shaare Zedek Medical Center, 9103102 Jerusalem, Israel.
14
Hematology-Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA.
15
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
16
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: charles.mullighan@stjude.org.

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.

PMID:
26321221
PMCID:
PMC4573904
DOI:
10.1016/j.ccell.2015.07.016
[Indexed for MEDLINE]
Free PMC Article

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