[PDF][PDF] Efficacy of retinoids in IKZF1-mutated BCR-ABL1 acute lymphoblastic leukemia

ML Churchman, J Low, C Qu, EM Paietta, LH Kasper… - Cancer cell, 2015 - cell.com
ML Churchman, J Low, C Qu, EM Paietta, LH Kasper, Y Chang, D Payne-Turner, MJ Althoff
Cancer cell, 2015cell.com
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 …
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.
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