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IKZF1 genetic variants may predispose children to ALL
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SAN DIEGO — Researchers have identified IKZF1 as a new pediatric acute lymphoblastic leukemia predisposition gene, according to study results presented during the late-breaking abstract session of the ASH Annual Meeting and Exposition.
IKZF1 germline risk variants appear to have roles in leukemia pathogenesis and treatment responsiveness, results showed.
“ALL is the most common childhood cancer, and a leading cause of cancer-related death in children,” Michelle L. Churchman, PhD, staff scientist at St. Jude Children’s Research Hospital, said during her presentation. “The subtypes of ALL are defined by chromosomal aberrations, particularly translocations, deletions and mutations. There is increasing evidence that some of the key variants that important in the development of ALL are heritable. Common germline polymorphisms have been identified in key transcription factors and tumor suppressors that have been associated with ALL risk.”
Recent sequencing of candidate genes known to be involved in cancer development showed 4.6% of children with leukemia have deleterious germline predisposing variants.
Churchman and colleagues initiated their research with a German family that had multiple cases of B-ALL. They identified a frameshift IKZF1 mutation in the proband’s germline DNA that truncated after the end-terminal zinc finger DNA binding domain.
“The same allele was discovered in his mother, sisters and a niece, and he had an uncle who died of ALL at the age of 6, nearly 40 years ago,” Churchman said. “Earlier this year there was a study that revealed Ikaros mutations in the germline of six families that had B-cell deficiencies, one of which had B-cell ALL. We discovered in our German family that our proband’s sisters and niece also had low B-cell numbers.”
IKZF1 encodes Ikaros, a transcription factor required for normal lymphocyte development. Somatic, noninherited alterations of IKZF1 have previously been shown to be a hallmark of high-risk ALL and poor prognosis. A variety of focal deletions and somatic mutations have been identified, which seem to cluster in the DNA binding domain and dimerization domain. The IK-6 isoform is the most deleterious focal deletion that has been observed.
Churchman and colleagues sought to identify the prevalence of inherited IKZF1 variants in sporadic ALL, and to evaluate whether any identified germline variants perturbed the function of Ikaros.
Researchers sequenced IKZF1 in the germline DNA of 5,008 children with ALL enrolled on Children’s Oncology Group and St. Jude Children’s Hospital frontline ALL studies.
Churchman and colleagues identified 33 variants in 44 patients, 27 of which were unique in altering a different amino acid in the protein.
After performing various studies to determine whether these variants were deleterious, the found four did not have any measurable effect in any of the assays, whereas the remained altered function in at least one assay, with ten being particularly damaging — M31V, R162P, H1637, D186fs, M306, M347V, C394, R423C, A434G and L449F.
Overall, three variants were frameshift of nonsense, leading to truncated IKZF1 proteins. Two of the remaining missense variants were located in the N-terminal DNA binding domain, one was in the C-terminal dimerization domain, and 22 were in other parts of the IKZF1 protein.
Using a Philadelphia-chromosome B-ALL model, researchers previously showed that Ikaros critical in the repression of adhesion genes and genes involved in differentiation. Abrogating the function of Ikaros loses its repressive ability results in mislocalization of leukemic cells in the bone marrow niche.
When researchers introduced IK-6 into BCR-ABL1 B cells they observed severe aggregation of leukemic cells. Enumerating the clusters by number and size, they found that some variants had little effect on the aggregation, some had a moderate effect, and some have severe aggregation, even more than IK-6.
Transplanting the cells into in vivo models showed the cells take on a spindle shape when they express IK-6, because they are adhering to the bone marrow stroma. Researchers found that the additional variants they identified also expressed the spindle shape, indicative that they also were adhering to the bone marrow.
Other in vivo analyses showed some variants resulted in a marked reduction in sensitivity of leukemic cells to dasatinib (Sprycel; Bristol-Myers Squibb, Otsuka).
“The penetrance of IKZF1 variants in ALL is an ongoing area of research,” Churchman said. “We are very interested why the C-terminal variants are so deleterious, when they are not in any of the known domains of Ikaros. Ultimately, we seek to address if these IKZF1 variants can be predictive of prognosis, and gain insight into the way in which these newly identified variants perturb Ikaros function” – by Alexandra Todak
Reference: Churchman ML, et al. Abstract LBA-2. Presented at: ASH Annual Meeting and Exposition; Dec. 3-6, 2016.
Disclosure: The researchers report no relevant financial disclosures.
Perspective
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Deepa Bhojwani, MD
This abstract brings forth a couple of important points. One is that in the past, we have not considered childhood acute lymphoblastic leukemia to be a disease that has an inherited predisposition. Over the last few years, more and more cases that have more than one patient in a family with ALL have been investigated with next-generation sequencing. Results from these studies tell us that we as clinicians need to dig a little more into family history, even if this may not be the kind of malignancy where we traditionally think of as having a family risk.
This paper has looked at germline IKZF1 variations. Researchers have shown that even though there were only a few patients out of several thousand who had inherent germline variations, it does prove that transcription factors, which are important in B-cell development, are important not only in somatic tissue but also in germline. This is the second important point made in this study. Researchers have further demonstrated what the functional consequences of these variants are and how they can contribute to the development of leukemia.
The third thing they have shown is that patients with a germline variation in IKZF1 are not only predisposed to ALL, but may be more resistant to chemotherapy.
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