Gene Mutation Identified That Can Trigger Lymphoblastic Leukemia

Some familial platelet disorders are associated with predisposition to leukemia, myelodysplastic syndrome (MDS) or dyserythropoietic anemia.

A family with autosomal dominant thrombocytopenia, high erythrocyte mean corpuscular volume (MCV) and two occurrences of B cell–precursor acute lymphoblastic leukemia (ALL) have been identified.


An international team of scientists led by those at Wayne State University (Detroit, MI, USA) screened 23 families with similar phenotypes using whole-exome sequencing to identify a heterozygous single-nucleotide change in the oncogene Ets Variant 6 (ETV6).

ETV6 was initially identified as a tumor suppressor by its involvement in somatic translocations in childhood leukemia. The team found three families with germline mutations in ETV6 and defects in hematopoiesis.

The investigators used a battery of methods to identify variants in the gene. These included exome sequencing carried out on the HiSeq 2000 system (Illumina; San Diego, CA, USA); platelet and bone marrow ribonucleic acid (RNA) sequencing; luciferase reporter assays which were analyzed using the Dual-Luciferase Reporter Assay kit (Promega; Madison, WI, USA). The team also used high-resolution laser immunofluorescence confocal microscopy using a Quorum spinning-disc confocal inverted epifluorescence microscope (Olympus, Shinjuku, Tokyo, Japan).

Of the 23 families with similar phenotypes the team identified two 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. The findings underscore a key role for ETV6 in platelet formation and leukemia predisposition.

Michael Callaghan, MD, an assistant professor of Pediatrics and coauthor of the study said, “Our findings underscore a key role for ETV6 in platelet formation and leukemia predisposition and 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 is that ETV6's job is to 'turn off' growth, but when you have this mutation, it can't turn it 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 study was published in the May 2015 issue of the journal Nature Genetics.

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Wayne State University 
Illumina 
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