Formin-Like Gene Expression in Chronic Lymphocytic Leukemia Is Associated with Unfavorable Prognostic Factors and Clinical Outcome

Formin proteins are large proteins evolutionarily conserved that govern cell shape, adhesion, cytokinesis, and morphogenesis by remodeling the actin and microtubule cytoskeletons. The human leukocyte formin, named as FMNL1, corresponds to an extended cDNA of the 5′-truncated KW-13 which was reported as a tumor-associated antigen in CLL, using a serologic identification by recombinant expression cloning (SEREX). In addition, FMNL1 co-immunoprecipitates with P-Akt in CLL cells, suggests that this protein may contribute to regulate cell survival. The aim of this study was to analyze the expression of FMNL1 in normal B-cell subsets and in a series of 73 patients (median age, 59 years; male/female 40/33; Binet A: 90.2%) with CLL. FMNL1 expression was analyzed by Western Blot, Immunohistochemistry and by Real-Time RT-PCR using expression in Jurkat as baseline. In normal lymphocytes subsets, FMNL1 was only expressed in memory B-cells, and in T-cells, whereas germinal center lymphocytes were negative. Among lymphoid B-cell malignancies, FMNL1 was expressed in mantle-cell lymphomas, Burkitt’s lymphomas and in DLBCL of GCB-type. In CLL cases mean of FMNL1 expression by QRT-PCR was 2.18 AU (SD, 1.01 AU). Using an arbitrary cut-off of 3.2 AU, cases with increased expression of FMNL1 were associated with a younger age at diagnosis (< 50 yrs), elevated lymphocyte count, high serum β2-microglobulin (β2-m) levels, increased ZAP-70 and CD38 expression, shorter time to progression, and shorter survival as compared to cases with low FMNL1 expression. No relationship was observed with genetic abnormalities. In summary, increased expression of FMNL1 gene couples with adverse clinical and biological parameters in patients with CLL. Finally, the interaction between FMNL1 and AKT protein in lymhoproliferative disorders is under investigation.