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

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

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83 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)343 - 356
Number of pages14
JournalCancer Cell
Volume28
Issue number3
DOIs
Publication statusPublished - 2015
Externally publishedYes

Cite this

Churchman, M., Low, J., Qu, C., Paietta, E. M., Kasper, L. H., Chang, Y., Payne-Turner, D., Althoff, M. J., Song, G., Chen, S-C., Ma, J., Rusch, M., McGoldrick, D. J., Edmonson, M. N., Gupta, P. C., Wang, Y-D., Caufield, W., Freeman, B. B., Panetta, J. C., ... Li, L. (2015). Efficacy of Retinoids in IKZF1-Mutated BCR-ABL1 Acute Lymphoblastic Leukemia. Cancer Cell, 28(3), 343 - 356. https://doi.org/10.1016/j.ccell.2015.07.016