Germline IKZF1 Variants Predispose Children to Developing B-ALL

Somatic genetic alterations in IKZF1, the gene encoding the lymphoid transcription factor IKAROS, are associated with a poor prognosis in patients with high-risk B-progenitor acute lymphoblastic leukemia (B-ALL). Churchman, Qian, te Kronnie, and colleagues identified germline IKZF1 variants that confer a predisposition to ALL. A germline mutation in IKZF1 predicted to result in a truncated protein was identified in a patient with BCR–ABL1-positive B-ALL. Examination of his family members identified the truncating variant in five individuals across three generations, including an uncle who had died of B-ALL. Based on these findings, germline DNA sequencing was performed on 4,963 children with newly diagnosed ALL, and 43 patients with IKZF1 variants were identified harboring 28 unique nonsilent exonic variants including missense, nonsense, and frameshift alterations. The IKZF1 variants were distributed throughout the gene and many were not predicted to be deleterious using in silico prediction tools. However, deleterious effects were observed in functional studies. Variants affecting the DNA-binding domain resulted in loss of IKAROS-mediated transcriptional repression and mislocalization to the cytoplasm. Other variants induced stem cell–like features and resulted in overexpression of cell adhesion molecules, thereby inducing aberrant cell–cell and cell–stroma interactions. Further, the majority of IKZF1 variants reduced sensitivity to the tyrosine kinase inhibitor dasatinib and chemotherapeutic drug dexamethasone in vitro and in vivo in ARF⁻ BCR–ABL1⁺ pre-B cells. Altogether, 22 of the identified IKZF1 variants were determined to be deleterious in at least one of the functional assays, with 6 variants considered to be benign. Collectively, these findings indicate that IKZF1 is a B-ALL susceptibility gene with multiple germline variants that contribute to disease susceptibility and influence leukemia drug response.

Churchman ML, Qian M, te Kronnie G, Zhang R, Yang W, Zhang H, et al. Germline genetic IKZF1 variation and predisposition to childhood acute lymphoblastic leukemia. Cancer Cell 2018 Apr 19 [Epub ahead of print].

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