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

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...

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Bibliographic Details
Published in:	Cancer cell Vol. 28; no. 3; p. 343
Main Authors:	Churchman, Michelle L, Low, Jonathan, Qu, Chunxu, Paietta, Elisabeth M, Kasper, Lawryn H, Chang, Yunchao, Payne-Turner, Debbie, Althoff, Mark J, Song, Guangchun, Chen, Shann-Ching, Ma, Jing, Rusch, Michael, McGoldrick, Dan, Edmonson, Michael, Gupta, Pankaj, Wang, Yong-Dong, Caufield, William, Freeman, Burgess, Li, Lie, Panetta, John C, Baker, Sharyn, Yang, Yung-Li, Roberts, Kathryn G, McCastlain, Kelly, Iacobucci, Ilaria, Peters, Jennifer L, Centonze, Victoria E, Notta, Faiyaz, Dobson, Stephanie M, Zandi, Sasan, Dick, John E, Janke, Laura, Peng, Junmin, Kodali, Kiran, Pagala, Vishwajeeth, Min, Jaeki, Mayasundari, Anand, Williams, Richard T, Willman, Cheryl L, Rowe, Jacob, Luger, Selina, Dickins, Ross A, Guy, R Kiplin, Chen, Taosheng, Mullighan, Charles G
Format:	Journal Article
Language:	English
Published:	United States 14.09.2015
Subjects:	Animals Cell Cycle Checkpoints - genetics Fusion Proteins, bcr-abl - genetics Humans Ikaros Transcription Factor - genetics Mice Mutation - genetics Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism Receptors, Retinoic Acid - metabolism Retinoids - metabolism
ISSN:	1878-3686, 1878-3686
Online Access:	Get more information
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1878-3686 1878-3686
DOI:	10.1016/j.ccell.2015.07.016