Germline Genetic IKZF1 Variation and Predisposition to Childhood Acute Lymphoblastic Leukemia

• Published in: Cancer cell Vol. 33; no. 5; pp. 937 - 948.e8
• Main Authors: Churchman, Michelle L., Qian, Maoxiang, te Kronnie, Geertruy, Zhang, Ranran, Yang, Wenjian, Zhang, Hui, Lana, Tobia, Tedrick, Paige, Baskin, Rebekah, Verbist, Katherine, Peters, Jennifer L., Devidas, Meenakshi, Larsen, Eric, Moore, Ian M., Gu, Zhaohui, Qu, Chunxu, Yoshihara, Hiroki, Porter, Shaina N., Pruett-Miller, Shondra M., Wu, Gang, Raetz, Elizabeth, Martin, Paul L., Bowman, W. Paul, Winick, Naomi, Mardis, Elaine, Fulton, Robert, Stanulla, Martin, Evans, William E., Relling, Mary V., Pui, Ching-Hon, Hunger, Stephen P., Loh, Mignon L., Handgretinger, Rupert, Nichols, Kim E., Yang, Jun J., Mullighan, Charles G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.05.2018
• Subjects: acute lymphoblastic leukemia; ALL; Animals; Child; drug response; familial leukemia; Female; Frameshift Mutation; Genetic Predisposition to Disease; Germ-Line Mutation; germline genetic variation; Humans; IKAROS; Ikaros Transcription Factor - genetics; Ikaros Transcription Factor - metabolism; IKZF1; immunodeficiency; Male; Mice; Neoplasm Transplantation; Pedigree; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - metabolism; predisposition; Sequence Analysis, DNA; drug response; ALL; germline genetic variation; acute lymphoblastic leukemia; IKAROS; predisposition; immunodeficiency; IKZF1; familial leukemia
• ISSN: 1535-6108; 1878-3686; 1878-3686
• DOI: 10.1016/j.ccell.2018.03.021

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. [Display omitted] •Germline coding IKZF1 variants are present in familial and sporadic B-precursor ALL•Most variants affect regions outside of known domains and perturb IKAROS function•Germline IKZF1 variants result in aberrant adhesion and bone marrow mislocalization•Germline IKZF1 variants result in reduced antileukemic drug sensitivity Churchman et al. identify 28 unique germline IKZF1 coding variants in 45 children with acute lymphoblastic leukemia. Many of these variants are not predicted to be damaging using in silico prediction tools, but functional tests reveal that the majority of them have deleterious effects on IKAROS function.