Hairy cell leukemia (HCL) is a rare, chronic form of leukemia, a cancer originating in the bone marrow’s blood-forming cells. It involves B-lymphocytes, a type of white blood cell normally responsible for producing antibodies. The disease is named for the cancerous B-cells, which develop fine, hair-like projections when viewed under a microscope. Research has identified a specific genetic error that acts as the direct driver of HCL development.
The Primary Genetic Driver
The definitive cause for nearly all cases of classic HCL is an acquired genetic mutation known as BRAF V600E. This mutation is not inherited but occurs spontaneously within a single B-lymphocyte. The change involves the BRAF gene, which provides instructions for a protein involved in cell growth and survival signaling.
The V600E notation refers to a specific alteration where the amino acid valine (V) is replaced by glutamic acid (E) at position 600. This change causes the BRAF protein to become permanently “switched on.” This constant activation continuously sends growth and survival signals, telling the B-lymphocyte to divide uncontrollably and avoid natural cell death.
The discovery of the BRAF V600E mutation in 2011 was a breakthrough. It is found in over 95% of HCL patients and defines the disease. Because this error is unique to HCL among B-cell cancers, its presence is a highly specific marker for diagnosing the classic form of the condition.
How the Hairy Cells Form and Multiply
The continuous signaling from the mutated BRAF protein transforms a normal B-lymphocyte into the malignant “hairy cell.” This runaway signaling pathway, known as the RAF-MEK-ERK pathway, is directly responsible for the characteristic irregular, hair-like projections that extend from the cell’s surface. These altered B-cells begin to multiply, accumulating primarily in the bone marrow and the spleen.
In the bone marrow, the cancerous cells crowd out the space needed for healthy blood cell production, a process called infiltration. This overcrowding leads to pancytopenia—a reduction in red blood cells, white blood cells, and platelets. The infiltration of the spleen often causes it to become enlarged (splenomegaly). The spleen sequesters these abnormal cells, and its enlargement can also contribute to the destruction of healthy blood cells. The resulting low counts of normal blood cells cause common HCL symptoms, such as fatigue from anemia and frequent infections.
Identifying Potential Risk Factors
While the BRAF V600E mutation is the internal cause of HCL, external and demographic factors are associated with an increased risk. HCL is significantly more common in men than in women, with the incidence rate about four times higher in males. Diagnosis typically occurs around 55 years old, as the disease is rarely seen in younger adults or children.
Environmental exposures have been implicated as potential risk factors. Studies suggest an association between HCL and chronic exposure to chemicals, particularly organic solvents like benzene and some agricultural pesticides. However, these remain associations, meaning they may increase susceptibility without being the direct cause of the genetic mutation. A family history of HCL or other blood disorders slightly increases risk, though the disease is not inherited.