Gene mutation triggers lymphoblastic leukemia
Recent research has "major implications" for understanding the genetic basis of several types of cancer, including leukemia.
After a nearly 10-year investigation, two medical researchers from the Children's Hospital of Michigan and the Wayne State University School of Medicine have identified a gene mutation that can trigger acute lymphoblastic leukemia (ALL) and several other cancers.
Madhvi Rajpurkar MD, hematologist and Professor of Pediatrics at the Children's Hospital of Michigan, joined an international team of genetic researchers to track down a mutation partly responsible for causing ALL. The findings are published in Nature Genetics.
A team of international investigators along with the duo from Wayne State University School of Medicine, have pinpointed a mutation allowing a lymphoblastic leukemia "precursor cell" to inititate blood cancer.
ALL attacks an early version of white blood cells manufactured in bone marrow. Investigators long suspected ALL was caused by a gene mutation. The ETV6 gene should "turn off" excessive blood-cell growth, but a mutation suppresses that mechanism allowing run-away blood cell growth.
The study began nearly a decade ago when Dr. Rajpurkar treated a child for low blood platelets, known as "congenital thrombocytopenia." When both the child and an aunt later developed ALL and several other family members were diagnosed with thrombocytopenia as well - Dr. Rajpurkar began to suspect a genetic mutation in the family.
What followed was a 10-year journey through the Human Genome labyrinth, as researchers worked with a growing number of genetic investigators to isolate and identify the mutation. They found it on the ETV6 gene that regulates blood cell growth rates in bone marrow.
"ETV6's job is to 'turn off' growth. But with this mutation, it can't turn anything off because it's in the wrong location. It's supposed to sit on top of the DNA strand and keep things from getting made. But instead, it's sitting in a different part of the cell. And that predisposes you to getting a (blood) cancer."
Michael Callaghan MD, Children's Hospital of Michigan, Department of Pediatrics, Wayne State University
Dr. Rajpurkar was "greatly pleased" that her decade of treating the Detroit family eventually led to a breakthrough. "I had told them that I didn't know what the family had," she said, "but that I would do my best to find out. Sometimes one has to accept uncertainty in the field of medicine, but persistence paid off!"
"Because of this finding, families will eventually be counseled regarding their risk for some kinds of cancer and targeted interventions will be devised and tested."
Steven E. Lipshultz MD, Pediatrician-in-Chief, The Children's Hospital of Michigan and chair of the Wayne State University School of Medicine Department of Pediatrics
Some familial platelet disorders are associated with predisposition to leukemia, myelodysplastic syndrome (MDS) or dyserythropoietic anemia1, 2. We identified a family with autosomal dominant thrombocytopenia, high erythrocyte mean corpuscular volume (MCV) and two occurrences of B cell–precursor acute lymphoblastic leukemia (ALL). Whole-exome sequencing identified a heterozygous single-nucleotide change in ETV6 (ets variant 6), c.641C>T, encoding a p.Pro214Leu substitution in the central domain, segregating with thrombocytopenia and elevated MCV. A screen of 23 families with similar phenotypes identified 2 with ETV6 mutations. One family also had a mutation encoding p.Pro214Leu and one individual with ALL. The other family had a c.1252A>G transition producing a p.Arg418Gly substitution in the DNA-binding domain, with alternative splicing and exon skipping. Functional characterization of these mutations showed aberrant cellular localization of mutant and endogenous ETV6, decreased transcriptional repression and altered megakaryocyte maturation. Our findings underscore a key role for ETV6 in platelet formation and leukemia predisposition.
The study is: "Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia,"
This work was supported by the Postle Family Chair in Pediatric Cancer and Blood Disorders (J.D.P.) and by U.S. National Institutes of Health grants HL112311 (A.S.W.) and GM103806 (J.W.R.).
About the Children's Hospital of Michigan, http://www.childrensdmc.org
For more than 125 years, the Children's Hospital of Michigan is the first hospital in the state dedicated exclusively to the treatment of children. With more than 40 pediatric medical and surgical specialties and services, the hospital is a leader internationally in neurology and neurosurgery, cardiology, oncology, and diagnostic services; it is ranked one of America's best hospitals for children by US News and World Report and Parent Magazine and is recognized for quality and safety by the Leapfrog Group. The Children's Hospital of Michigan is one of eight hospitals operated by the Detroit Medical Center (DMC).
About Wayne State University, http://www.wayne.edu
Wayne State University is a premier urban research institution offering more than 400 academic programs through 13 schools and colleges to nearly 32,000 students. The school educates more than 1,200 medical students. In addition to undergraduate medical education, the school offers master's degree, Ph.D. and M.D.-Ph.D. programs in 14 areas of basic science to about 400 students annually.
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