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

Abstract

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.

• Authors: Michelle L Churchman, Maoxiang Qian, Geertruy Te Kronnie, Ranran Zhang, Wenjian Yang, Hui Zhang, Tobia Lana, Paige Tedrick, Rebekah Baskin, Katherine Verbist, Jennifer L Peters, Meenakshi Devidas, Eric Larsen, Ian M Moore, Zhaohui Gu, Chunxu Qu, Hiroki Yoshihara, Shaina N Porter, Shondra M Pruett-Miller, Gang Wu, Elizabeth Raetz, Paul L Martin, W Paul Bowman, Naomi Winick, Elaine Mardis, Robert Fulton, Martin Stanulla, William E Evans, Mary V Relling, Ching-Hon Pui, Stephen P Hunger, Mignon L Loh, Rupert Handgretinger, Kim E Nichols, Jun J Yang, Charles G Mullighan
• Journal: Cancer cell (Cancer Cell) Vol. 33 Issue 5 Pg. 937-948.e8 (05 14 2018) ISSN: 1878-3686 [Electronic] United States
• PMID: 29681510 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• IKZF1 protein, human
• Ikaros Transcription Factor

Topics

• Animals
• Child
• Female
• Frameshift Mutation
• Genetic Predisposition to Disease
• Germ-Line Mutation
• Humans
• Ikaros Transcription Factor (genetics, metabolism)
• Male
• Mice
• Neoplasm Transplantation
• Pedigree
• Precursor B-Cell Lymphoblastic Leukemia-Lymphoma (genetics, metabolism)
• Sequence Analysis, DNA