Germline Genetic IKZF1 Variation and Predisposition to Childhood Acute Lymphoblastic Leukemia

IKZF1, which encodes the lymphoid transcription factor IKAROS, is frequently targeted by somatic deletions and mutations in high-risk Bprogenitor acute lymphoblastic leukemia (ALL) and is associated with poor prognosis. Somatic IKZF1 alterations result in the acquisition of stem celllike features, overexpression of adhesion molecules causing aberrant cellcell and cell-stroma interaction, and decreased sensitivity to tyrosine kinase inhibitors. Here we report coding IKZF1 variation in familial childhood ALL and 1% of presumed sporadic B-ALL, with 28 unique germline IKZF1 variants in 45 children. The majority of variants adversely affected IKZF1 function and drug responsiveness of leukemic cells. These results identify IKZF1 as a leukemia predisposition gene, and emphasize the importance of germline genetic variation in the development of both familial and sporadic ALL.