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

2015; Cell Press; Volume: 28; Issue: 3 Linguagem: Inglês

10.1016/j.ccell.2015.07.016

1878-3686

Michelle L. Churchman, Jonathan Low, Chunxu Qu, Elisabeth Paietta, Lawryn H. Kasper, Yunchao Chang, Debbie Payne-Turner, Mark J. Althoff, Guangchun Song, Shann-Ching Chen, Jing Ma, Michael Rusch, Dan McGoldrick, Michael N. Edmonson, Pankaj Gupta, Yong‐Dong Wang, William Caufield, Burgess B. Freeman, Lie Li, John C. Panetta, Sharyn D. Baker, Yung‐Li Yang, Kathryn G. Roberts, Kelly McCastlain, Ilaria Iacobucci, Jennifer L. Peters, Victoria E. Centonze, Faiyaz Notta, Stephanie M. Dobson, Sasan Zandi, John E. Dick, Laura J. Janke, Junmin Peng, Kiran Kodali, Vishwajeeth Pagala, Jaeki Min, Anand Mayasundari, Richard T. Williams, Cheryl L. Willman, Jacob M. Rowe, Selina M. Luger, Ross A. Dickins, R. Kiplin Guy, Taosheng Chen, Charles G. Mullighan,

Acute Myeloid Leukemia Research

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.