COMMENTS AND RESPONSES bcl-2 Rearrangement in Mixed Cryoglobulinemia

TO THE EDITOR: In their interesting report, Zignego and colleagues (1) observed that the translocation t(14;18) involving the bcl-2 oncogene is much more common in patients with hepatitis C virus infection and mixed cryoglobulinemia, particularly those with type II disease. They measured Bcl-2 protein expression in the peripheral blood mononuclear cells (PBMCs) of two patients carrying the translocation and two controls and found overexpression of Bcl-2 protein in the former. In their Figure 3, they also showed that Bcl-2 expression in PBMCs is largely confined to B cells. However, when Bcl-2 expression is compared in PBMCs, the number of B cells in the sample must be taken into account. My colleagues and I (2) examined Bcl-2 expression in patients with a disorder characterized by chronic B-cell proliferation, persistent polyclonal B-cell lymphocytosis (which is an expansion of memory B cells) (3). In persistent polyclonal B-cell lymphocytosis, a substantial number of peripheral blood B cells carry the t(14;18) translocation (1 to 3 in 1000, as measured by quantitative real-time polymerase chain reaction). When we compared unpurified PBMCs from patients with persistent polyclonal B-cell lymphocytosis and those from controls, we found that the patients had overexpression of Bcl-2 protein. However, when we compared purified B cells from patients and controls, this was no longer true, demonstrating that the apparent overexpression of Bcl-2 was due to the different number of B cells in the PBMCs of the two groups (50% to 80% vs. 5% to 15%, respectively) (2). Since there can be also an expansion of peripheral blood B cells in type II cryoglobulinemia (4), Zignego and colleagues should have normalized the numbers of B cells in their samples when comparing Bcl-2 expression with that of normal controls. In addition, persistent polyclonal B-cell lymphocytosis reminds us to interpret the presence of the translocation t(14;18) with caution. In contrast to patients with hepatitis C virus infection and cryoglobulinemia, no clear case of transformation to frank lymphoma has been observed in patients with this obscure disorder.