Scientists looked for HCL-associated mutations by performing massively parallel sequencing of the whole exome of leukemic and matched normal cells purified from the peripheral blood of an index patient with HCL. Findings were validated by Sanger sequencing in 47 additional patients with HCL.

Hairy-cell leukemia (HCL) is a well-defined clinicopathological entity whose underlying genetic lesion is still obscure. The single mutation occurred in every patient in a cohort with hairy cell leukemia, suggesting that targeting the mutation could have major implications for treating the disease, Italian investigators reported.

Gene-expression profiling and genome-wide single-nucleotide polymorphism genotyping failed to pinpoint any recurrent genetic alterations in HCL.

Brunangelo Falini, MD , Enrico Tiacci, MD , and colleagues of the University of Perugia (Italy) using the more powerful approach to examining the genetic basis of cancer: genome-wide massively parallel sequencing of tumor and normal cells from the same patient. They sought to identify recurrent somatic mutations in protein-coding genes, with the goal of gaining more insight into the origin of the disease and identifying new options for diagnosis and treatment.

A consequence of this discovery may be that specific drugs/molecules can be developed that inhibit the activated, mutated BRAF gene, thereby preventing continuous stimulation of leukemic cells to divide. The first laboratory results employing these specific inhibitors show promising results.

Hairy cell leukemia is characterized by the piling up of leukemic cells in the bone marrow with a lack of production of normal blood cells, which might be life-threatening, as well as a large spleen, which may lead to significant complaints to the patients involved.

"The BRAF V600E mutant is a potential therapeutic target in patients with hairy cell leukemia who do not have a response (or have a suboptimal response) to initial therapy with purine analogs, as well as in patients with repeated relapses or unacceptable toxic effects," Dr. Falini and coauthors wrote in conclusion.

"Notably, BRAF V600E inhibitors have shown remarkable activity in patients with BRAF-mutated metastatic melanoma. These results, along with our in vitro finding that a specific active BRAF inhibitor causes MEK and ERK dephosphorylation in primary hairy cell leukemia cells, warrant the clinical testing of active BRAF inhibitors."

The findings were published online in the New England Journal of Medicine (NEJM) on June 11, 2011.

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