Earlier this week, during the annual meeting of the European Hematology Association (EHA) in London, professor Enrico Tiacci, M.D. from the Institute of Hematology in Perugia, Italy presented groundbreaking news on the cause of a specific, rare subtype of leukemia, so-called hairy cell leukemia (HCL). The average age of diagnosis is 55 and the diseases affects men more often than women.

?With modern genetic technology we have discovered that in all patients with hairy cell leukemia one specific gene in the DNA in the cell nucleus, the BRAF gene, has undergone an irreversible mutation. Through this a cascade of events occurs which lead to continuous division/proliferation of the malignant cells in hairy cell leukemia?, Tiacci said.

The BRAF gene is a member of the Raf kinase family of serine/threonine-specific protein kinases which plays a role in regulating the MAP kinase / ERKs signaling pathway. Mutations of this gene, which affects cell division, differentiation, and secretion, has been implicated in various forms of cancer, including non-Hodgkin lymphoma, colorectal cancer, malignant melanoma, thyroid carcinoma, non-small cell lung carcinoma, and adenocarcinoma.

The researchers observed that the BRAF V600E mutation inpatients with hairy cell leukemia was not involved in patients with other types of peripheral B-cell lymphomas or leukemias who carried the BRAF V600E variant, including 38 patients with splenic marginal-zone lymphomas or unclassifiable splenic lymphomas or leukemias. They also noted that the hairy cell leukemia cells expressed phosphorylated MEK and ERK, the downstream targets of the BRAF kinase, indicating a constitutive activation of the RAF?MEK?ERK mitogen-activated protein kinase pathway in HCL.

B-cell leukemia
Hairy cell leukemia, a a slow-growing form chronic B-cell leukemia, is characterized by an accumulation of lymphocytesin the bone marrow, blood and an spleen with a lack of production of normal blood cells.

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Because these lymphocytes are abnormal, they do not fight disease and infection, and eventually may crowd out the normal cells. This process may be life-threatening and leads to a significant number of complaints.

Hair-like projections
The disease is called ?hairy cell leukemia? because when seen under a microscope the abnormal lymphocytes have projections, coming from the cell’s surface, that look like hair.

New treatment options: a promissing future
The finding that the BRAF V600E mutation was present in all patients with HCL who were evaluated in the study may have implications for the pathogenesis, diagnosis, and future therapy of HCL.

As a direct result of this discovery new specific drugs and molecules may be developed that inhibit the activated, mutated BRAF gene, thereby preventing continuous stimulation of leukemic cells to divide. Some of the first in vitro laboratory results employing specific inhibitors such as PLX-4720 (Plexxicon), a specific inhibitor of BRAF, led to a very promissing marked decrease in phosphorylated ERK and MEK.

For more information:
Tiacci E, Trifonov V, Schiavoni G, Holmes A, Kern W, et al. BRAF Mutations in Hairy-Cell Leukemia. This article (10.1056/NEJMoa1014209) was published on June 11, 2011, in the online edition of the New England Journal of Medicine.

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