IKZF1 Gene Mutations Found to Increase Hereditary Risk for Acute Lymphocytic Leukemia in Children
variants affect a protein involved in white blood cell development
Published on: December 06, 2016
(San Diego, December 6,
2016) – A late-breaking abstract being presented today during the
58th American Society of Hematology (ASH) Annual Meeting and Exposition in San
Diego identifies inherited genetic mutations in the gene IKZF1 that confer a higher likelihood of developing pediatric acute
lymphocytic leukemia (ALL). The findings are among the latest evidence to point
to a strong inherited genetic basis of ALL risk in children. Some of the
variants identified also appear to reduce cancer cells’ sensitivity to a
chemotherapy drug used to treat some types of ALL, potentially contributing to
“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,” said lead study author Michelle
L. Churchman, PhD, of St. Jude Children’s Research Hospital in Memphis. “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
Overall, about 85
percent of children survive for at least five years after being diagnosed with ALL,
a cancer affecting the lymphocytes, a type of white blood cell. Only a handful
of other genes have been identified that appear to be associated with a
predisposition to the disease. 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. The IKZF1 gene encodes Ikaros, a protein
with essential roles in lymphocyte development. Previous studies have found defects
in IKZF1 in leukemia cells linked
with some high-risk forms of ALL that respond poorly to treatment, such as
BCR-ABL1 (Philadelphia chromosome) ALL.
sequenced the IKZF1 gene in germline DNA
from normal blood samples of more than 5,000 children with ALL treated by St.
Jude Children’s Research Hospital and other collaborating institutions in the
Children’s Oncology Group and identified 28 gene variants. They then introduced
these variant forms of IKZF1 into cultured
cells to gauge their effects on activity of the Ikaros protein, cell growth and
behavior, and response to chemotherapeutic agents. 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 chemotherapy drug dasatinib, a drug commonly used to
treat high-risk forms of ALL such as BCR-ABL1.
“Leukemia running in
families may be more common than was previously appreciated,” said Dr.
Churchman. “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.”
The team plans to continue
to study the clinical outcomes of patients with IKZF1 variants, further assess the degree to which these mutations increase
the risk of ALL in families, and integrate different types of genomic studies
for a more complete picture of how these mutations are inherited.
study was funded by ALSAC of St. Jude, the National Cancer Center and National
Institute for General Medical Science of the National Institutes of Health, and
grants from the Leukemia & Lymphoma Society and St. Baldrick’s Foundation.
Michelle L. Churchman, PhD, St.
Jude Children’s Research Hospital, Memphis, Tenn. will present this study, titled
“Germline Genetic Variation in IKZF1 and Predisposition to
Childhood Acute Lymphoblastic Leukemia,” as a late-breaking abstract
(LBA-2) on Tuesday, December 6 in Hall AB of the San Diego Convention Center.
For the complete
annual meeting program and abstracts, visit www.hematology.org/annual-meeting.
Follow @ASH_hematology and #ASH16 on Twitter and like ASH on Facebook for the
most up-to-date information about the 2016 ASH Annual Meeting.
The American Society
of Hematology (ASH) (www.hematology.org) is the world's largest professional
society of hematologists dedicated to furthering the understanding, diagnosis,
treatment, and prevention of disorders affecting the blood. For more than 50 years,
the Society has led the development of hematology as a discipline by promoting
research, patient care, education, training, and advocacy in hematology. The
Society publishes Blood (www.bloodjournal.org),
the most cited peer-reviewed publication in the field, as well as the newly
launched, online, open-access journal, Blood
Richele Keas, FleishmanHillard
Stephen Fitzmaurice, ASH
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