In a forthcoming issue of Blood there will be an article on FCRL2, a new prognsotic factor for CLL.
The discovery that patients with chronic lymphocytic leukemia (CLL) who showed somatic hypermutation of their immunoglobulin heavy chain variable region genes (IGHV) lived on average three times longer than those who did not (1, 2) revolutionized the study of CLL and has greatly influenced the design and understanding of clinical trials. Assaying for such mutations seems complicated and the prospect is sufficiently intimidating to deter most routine laboratories from offering the test. Instead there has been a search for a surrogate marker, especially one that can be assayed by a familiar technique such as flow cytometry.
Originally, the expression of CD38 looked promising (1), but that was shown to be discordant with IGHV mutations in up to 30% of cases; so much so that it could be regarded as an independent prognostic factor. Moreover it could change during the course of the disease (3). Gene expression profiling of the two subtypes of CLL suggested that the Syk family tyrosine kinase gene ZAP-70 was the best discriminator between them (4), but translating this finding into a flow cytometry test has proved troublesome and none of the many possible assays has gained universal acceptance. One commonly used assay shows only 77% concordance with IGHV mutations (5).
The immunoglobulin superfamily is a large group of cell surface and soluble proteins that share structural features with immunoglobulin molecules, and includes receptors, co-receptors and co-stimulatory molecules. The well-known receptors for the Fc portion of immunoglobulin are members of this family. Recently a large family of Fc receptor-like molecules (FCRL) with preferential expression on B lymphocytes has been discovered (6). Genes coding for them localize to chromosome 1q21. There is no convincing evidence that they bind immunoglobulin and so far they lack ligands. In a coming issue of Blood, Li and colleagues have demonstrated that some of the FCRL are expressed more densely on CLL cells from patients with mutated IGHV genes than on those from patients with unmutated IGHV genes. A flow cytometric assay using a monoclonal antibody against FCRL2 and measuring mean fluorescence intensity (MFI) discriminated between CLL cells with mutated and unmutated IGHV genes with a concordance of 94.4%. Among 107 patients with CLL, median time to first treatment was more than four times as long for patients whose cells expressed FCRL2 with an MFI ratio of 4.2 or greater. FCRL2 seems to be stably expressed over time.
Should measurement of FCRL2 expression replace IGHV mutations as a prognostic marker? We must first see confirmation of these results in a rather larger series of patients, but given that DNA sequencing is cheaply available from commercial sources and that matching the sequence to the database is performed by a computer program, one wonders why so few laboratories have established the assay for IGHV mutations. In any event discordances between the various prognostic markers and the clinical picture promise to give us a clearer insight into why some cases of CLL progress and some do not.
1. Damle RN, Wasil T, Fais F et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood. 1999;94:1840-1847.
2. Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999;94:1848-1854.
3. Hamblin TJ, Orchard JA, Ibbotson RE et al. CD38 expression and immunoglobulin variable region mutations are independent prognostic variables in chronic lymphocytic leukemia, but CD38 expression may vary during the course of the disease. Blood. 2002;99:1023-1029.
4. Wiestner A, Rosenwald A, Barry TS et al. ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile. Blood. 2003;101:4944-4951.
5. Rassenti LZ, Huynh L, Toy TL et al. ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. N Engl J Med. 2004;351:893-901.
6. Davis RS. Fc receptor-like molecules. Annu Rev Immunol. 2007;25:525-560.