IKZF1 Identified as New ALL Predisposition Gene

A study of pediatric acute lymphoblastic leukemia (ALL) has identified IKZF1 as a new ALL predisposition gene that may play a role both in leukemia pathogenesis and treatment responsiveness. Genetic mutations in the IKZF1 gene confer a higher likelihood of developing pediatric ALL, according to results (abstract LBA-2) presented by Michelle L. Churchman, PhD, of St. Jude Children’s Research Hospital, at the 58th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, held December 3–6.

“The genetic variants help explain why these children develop leukemia and also inform potential risk for ALL in family members who carry the same defective version of IKZF1,” Churchman said in a press release. “If patients are identified as having one of these deleterious IKZF1 mutations, then that could potentially inform their treatment, whether family members need to get screened, or other clinical decisions.” 

The new study was initiated after multiple cases of pediatric ALL were reported in a single family in Germany and a genetic analysis of the family members pointed to an inherited mutation in IKZF1 as a possible contributor. According to the abstract, IKZF1 encodes the founding member of the Ikaros family of zinc finger transcription factors, and is a critical regulator of lymphoid development. IKZF1 is frequently targeted by somatic deletions and mutations in high-risk B-ALL, particularly Ph+ and Ph-like ALL, and is associated with poor outcome.

In this study, the researchers wanted to characterize germline IKZF1 genetic variations to determine the extent to which they contribute to predisposition to ALL. To do that they sequenced IKZF1 in germline DNA taken from 5,008 children with ALL enrolled in the Children’s Oncology Group and St. Jude Children’s Research Hospital front-line ALL trials. They identified 28 gene variants. Among these variants, three were frameshift or nonsense resulting in truncated IKZF1 proteins. Of the remaining missense variants, two were located within the N-terminal DNA-binding domain, one in the C-terminal dimerization domain, and 22 in other parts of IKZF1 protein with clustering proximal to the C-terminal zinc fingers. 

They then examined each variant for its effects on transcriptional repression, DNA-binding, cellular localization, homodimerization, and leukemic cell adhesion in mouse BCR-ABL1 Arf^null B-ALL cells and/or in HEK 293T cells.

The results showed that most of the gene variants caused abnormalities conducive to the development of leukemia, such as increased cellular aggregation and “stickiness” of cells in the bone marrow. Several variants significantly reduced the sensitivity of leukemic cells to the tyrosine kinase inhibitor drug dasatinib. 

“Leukemia running in families may be more common than was previously appreciated,” Churchman said. “This is now a very active area of research, and I think we’re looking at the tip of the iceberg in terms of genetic predisposition to this type of leukemia, and maybe other types as well. We now have a handful of genes identified, and I think that there will be more to come.”