Germline Genetic IKZF1 Variation and Predisposition to Childhood Acute Lymphoblastic Leukemia.

Gu Z, Yoshihara H, Hunger SP, Verbist K, Qian M, Wu G, Yang W, Loh ML, Tedrick P, Baskin R, Bowman WP, Martin PL, Evans WE, Larsen E, Moore IM, Relling MV, Mullighan CG, Zhang R, Devidas M, Nichols KE, Churchman ML, Lana T, Pui CH, Mardis E, Fulton R, Pruett-Miller SM, Yang JJ, Zhang H, Handgretinger R, Te Kronnie G, Peters JL, Raetz E, Stanulla M, Porter SN, Qu C, Winick N
Cancer Cell in press 04/16/2018


Somatic genetic alterations of IKZF1, which encodes the lymphoid transcription factor IKAROS, are common in high-risk B-progenitor acute lymphoblastic leukemia (ALL) and are associated with poor prognosis. Such alterations result in the acquisition of stem cell-like features, overexpression of adhesion molecules causing aberrant cell-cell and cell-stroma interaction, and decreased sensitivity to tyrosine kinase inhibitors. Here we report coding germline IKZF1 variation in familial childhood ALL and 0.9% of presumed sporadic B-ALL, identifying 28 unique 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.

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