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 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. •Ikzf1 alterations confer stem cell-like properties and increased cell adhesion in BCR-ABL1 ALL•IKZF1-altered BCR-ABL1 leukemias display reduced responsiveness to dasatinib•Retinoids reverse the effects of Ikzf1 alterations, partially by induction of IKZF1•Retinoids potentiate the activity of dasatinib in human and mouse BCR-ABL1 ALL Churchman et al. show that Ikzf1 alterations in mouse models of BCR-ABL1 leukemia confer stem cell-like features and poor responsiveness to ABL kinase inhibitor therapy. Retinoids reverse these phenotypes in part by inducing expression of wild-type IKZF1, providing therapeutic potential.