Germline Genetic IKZF1 Variation and Predisposition to Childhood Acute Lymphoblastic Leukemia.
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.
Churchman, ML; Qian, M; Te Kronnie, G; Zhang, R; Yang, W; Zhang, H; Lana, T; Tedrick, P; Baskin, R; Verbist, K; Peters, JL; Devidas, M; Larsen, E; Moore, IM; Gu, Z; Qu, C; Yoshihara, H; Porter, SN; Pruett-Miller, SM; Wu, G; Raetz, E; Martin, PL; Bowman, WP; Winick, N; Mardis, E; Fulton, R; Stanulla, M; Evans, WE; Relling, MV; Pui, C-H; Hunger, SP; Loh, ML; Handgretinger, R; Nichols, KE; Yang, JJ; Mullighan, CG
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