Abstract
Ikzf1 alterations induce stem cell–like properties in BCR–ABL1+ ALL that are abrogated by retinoids.
Major finding: Ikzf1 alterations induce stem cell–like properties in BCR–ABL1+ ALL that are abrogated by retinoids.
Mechanism: Retinoids inhibit adhesion and self-renewal in part by inducing wild-type IKZF1 expression.
Impact: Retinoids improve the therapeutic response to dasatinib in BCR–ABL1+ ALL harboring IKZF1 alterations.
Acute lymphoblastic leukemia (ALL) results from the overproliferation of immature lymphoid cells that fail to differentiate into mature lymphocytes. Deletions or mutations in IKZF1, which encodes the lymphoid transcription factor IKAROS, are a hallmark of BCR–ABL1+ ALL, but the effects of these alterations on disease progression and therapeutic response are not well understood. Churchman and colleagues found that expression of the dominant-negative IK6 isoform of IKZF1 (in which the DNA-binding zinc fingers are deleted) and deletion of Arf cooperated to drive formation of B-progenitor lymphoid ALL in a mouse transplant model of BCR–ABL1+ leukemia. In addition, expression of IK6 or Ikzf1 haploinsufficiency reduced the therapeutic response of BCR–ABL1+ ALL to the tyrosine kinase inhibitor (TKI) dasatinib. Analysis of the transcriptome and proteome of Ikzf1-altered Arf−/−; BCR–ABL1+ pre-B cells revealed overexpression of multiple adhesion molecules that are transcriptionally repressed by IKZF1, consistent with the increased bone marrow stromal adherence of Ikzf1-altered cells. Furthermore, Ikzf1 alterations resulted in the enrichment of stem cell–related genes and enhanced self-renewal in vitro. Given the association between stem cell–like and adhesive properties with poor response to TKIs, the authors performed a high-throughput screen to identify TKI-sensitizing agents that abolish the self-renewal capacity of IK6-expressing Arf−/−; BCR–ABL1+ ALL cells. Addition of retinoid compounds targeting different retinoid receptors arrested cell proliferation without direct cytotoxicity and abrogated the stem cell–like phenotype of Ikzf1-altered pre-B cells. This effect resulted, in part, from retinoid-mediated induction of wild-type IKZF1, but not IK6, in BCR–ABL1+ leukemia cells. Moreover, co-administration of dasatinib with the synthetic retinoid bexarotene increased the response to dasatinib and prolonged the survival of mice bearing IKZF1-altered leukemia. These results characterize the role of IKZF1 alterations in high-risk ALL and highlight a potential therapeutic strategy to improve therapeutic responses in patients with BCR–ABL1+ ALL.
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