St Jude Children’s Research Hospital - Department of Pharmaceutical Sciences; Guangzhou Medical University, First Affiliated Hospital, Department of Pediatrics
University of Florida - Department of Biostatistics; University of Florida - College of Medicine; University of Florida - College of Public Health and Health Professions
St Jude Children’s Research Hospital - Department of Pharmaceutical Sciences; St Jude Children’s Research Hospital - Hematological Malignancies Program
St Jude Children’s Research Hospital - Department of Pharmaceutical Sciences; St Jude Children’s Research Hospital - Hematological Malignancies Program
University of California, San Francisco (UCSF) - Department of Pediatrics; University of California, San Francisco (UCSF) - Benioff Children’s Hospital; University of California, San Francisco (UCSF) - Helen Diller Family Comprehensive Cancer Center
St Jude Children’s Research Hospital - Department of Pharmaceutical Sciences; St Jude Children’s Research Hospital - Hematological Malignancies Program
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.
Churchman, Michelle L. and Qian, Maoxiang and Kronnie, Geertruy te and Zhang, Ranran and Yang, Wenjian and Zhang, Hui and Lana, Tobia and Tedrick, Paige and Baskin, Rebekah and Verbist, Katherine and Peters, Jennifer L. and Devidas, Meenakshi and Raetz, Elizabeth and Larsen, Eric and Martin, Paul L. and Bowman, W. Paul and Winick, Naomi and Mardis, Elaine and Fulton, Robert and Stanulla, Martin and Evans, William E. and Relling, Mary V. and Pui, Ching-Hon and Hunger, Stephen P. and Loh, Mignon L. and Handgretinger, Rupert and Nichols, Kim E. and Mullighan, Charles G. and Yang, Jun J., Germline Genetic IKZF1 Variation and Predisposition to Childhood Acute Lymphoblastic Leukemia (2018). Available at SSRN: https://ssrn.com/abstract=3155671 or http://dx.doi.org/10.2139/ssrn.3155671
This version of the paper has not been formally peer reviewed.
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