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ETV6 Mutation May Trigger Lymphoblastic Leukemia

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Key Points

  • Researchers identified a mutation in ETV6 that prevents the gene from “turning off” blood cell growth.
  • The findings underscore a key role for ETV6 in platelet formation and leukemia predisposition.
  • The discovery may eventually allow for families to be counseled regarding their risk for some types of cancer and for the development of targeted interventions.

The results of a nearly 10-year investigation that identified a key gene mutation that can trigger acute lymphoblastic leukemia (ALL) and several other types of cancer were recently published by Noetzli et al in Nature Genetics.

The findings have, for the first time, pinpointed a mutation that allows a lymphoblastic leukemia precursor to set the biochemical stage for the blood disorder. Investigators have long suspected ALL is caused in part by a mutation in a gene that is supposed to “turn off” excessive blood cell growth. When the mutation suppresses the controlling mechanism that regulates the runaway growth, leukemia is often the result.

Roots of the Research

The study began nearly a decade ago when Madhvi Rajpurkar, MD, treated a child at the Children's Hospital of Michigan for congenital thrombocytopenia. When both the child and an aunt later developed ALL—even as several other family members were diagnosed with thrombocytopenia—Dr. Rajpurkar began to suspect that there might be a genetic mutation at work in the family. For the next 10 years, researchers worked with a growing number of genetic investigators to isolate and identify the mutation in a gene, ETV6, which regulates growth rates in bone marrow.

A key breakthrough took place when a nationally recognized expert in gene mutation—University of Colorado physician-researcher Jorge Di Paola, MD—joined Dr. Rajpurkar, Michael Callaghan, MD, of Wayne State University, and many other investigators in the effort to uncover the flaw in ETV6.

Research Findings

While noting that “our findings underscore a key role for ETV6 in platelet formation and leukemia predisposition,” the study's authors concluded that the mutation occurs through “aberrant cellular localization” of the gene, which can result in “decreased transcriptional repression” during white blood cell formation.

“What we think that means,” Dr. Callaghan said, “is that ETV6's job is to ‘turn off’ growth, but when you have this mutation, it can't ‘turn off,’ because it's in the wrong place. It's usually supposed to sit on the DNA and keep things (including cancer) from getting made, but when you have this mutation, instead of sitting on the DNA, it's sitting in a different part of the cell—and that predisposes you to getting a [blood] cancer.”

The Children's Hospital of Michigan Pediatrician-in-Chief and Chair of the Wayne State University School of Medicine Department of Pediatrics Steven E. Lipshultz, MD, said the breakthrough was “hugely important,” because it resulted in “a new association [between a genetic mutation and leukemia] that can now be scanned for. 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.”

Dr. Di Paola; Christopher Porter, MD, of the University of Colorado; and Walter Kahr, MD, PhD, of the Hospital for Sick Children, are the corresponding authors of the Nature Genetics article.

This work was supported by the Postle Family Chair in Pediatric Cancer and Blood Disorders and by the National Institutes of Health.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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