Photo by Rhoda Baer
New research suggests that heritable mutations in the gene ETV6 can predispose people to acute lymphoblastic leukemia (ALL).
Somatic mutations in ETV6 have previously been implicated in the development of ALL and other hematologic malignancies.
The new study, published in Nature Genetics, has shown that germline mutations in ETV6 are associated with thrombocytopenia, red blood cell (RBC) macrocytosis, and predisposition to ALL.
The research began with a family (family 1) that had autosomal dominant thrombocytopenia (67,000-132,000 platelets/μL), high RBC mean corpuscular volume (MCV, 92.5-101.5 fl), and 2 cases of B-cell-precursor ALL.
“All of them had big red blood cells, low platelet counts, and propensity to bleed,” said study author Christopher Porter, MD, of the University of Colorado Denver.
This familial link to abnormal blood dynamics and predisposition to ALL implied a common genetic denominator. To find it, the researchers performed whole-exome sequencing and found a heterozygous single-nucleotide change in ETV6, c.641C>T, encoding a p.Pro214Leu substitution in the central domain.
The researchers then screened 23 other families with similar phenotypes as the first and identified 2 families with ETV6 mutations.
One family (family 2) had members with platelet counts ranging from 44,000 to 115,000 platelets/μL, RBC MCVs ranging from 88 to 97 fl, and a member with ALL. All affected family members had a c.641C>T mutation identical to the one identified in family 1.
Another family (family 3) had members with platelet counts ranging from 99,000 to 101,000 platelets/μL and RBC MCVs ranging from 93 to 98 fl but no malignancies. Members of this family had a c.1252A>G transition producing a p.Arg418Gly substitution in the DNA-binding domain, with alternative splicing and exon skipping.
The researchers said these mutations partially disrupt ETV6 transcriptional repression in vitro and cause aberrant cytoplasmic localization of both mutant and endogenous ETV6, suggesting a dominant-negative effect. The mutations also impair megakaryocyte development and proplatelet formation in culture.
Dr Porter and his colleagues noted that another team of researchers recently discovered germline missense mutations in ETV6 in 3 unrelated families. Dr Porter’s group hopes future work will show the prevalence of germline mutations in ETV6.
“It’s not common in a general population, but we think it might be much more common in people who develop ALL,” Dr Porter said. “[Our] paper highlights this gene in the development of leukemia. By studying this mutation, we should be able to gather a better understanding of how leukemia develops.”
