Clonal T Cell Expansion in High Risk Myelodysplastic Syndrome (MDS).

Myelodysplastic Syndrome (MDS), a hematologic malignancy, is associated with cytogenetic and molecular abnormalities in maturing hematopoietic cells that occurs in 40–70% of cases. These abnormalities directly contribute to increased apoptosis and ineffective hematopoiesis of erythroid and myeloid progenitors while frequently sparing lymphoid subsets. In addition to these direct mechanisms of hematopoietic failure, failed hematopoiesis mediated indirectly by an autoimmune mechanism has been suggested to have importance in a subset of patients with the disease. Autoimmune-mediated bone marrow suppression is suggested by the positive outcome of several clinical trials using immunosuppressants. Depletion of autoreactive T cells with deleterious effects on bone marrow formation is considered the immunologic foundation for these therapeutic responses and bone marrow hypocellularity has been indicated as the best predictor of response. Antigen-driven expansion of immunodominant T cell clones can lead to overrepresentation of cells expressing individual T Cell Receptors (TCRs), which is known as TCR skewing. Treatment of hypocellular MDS patients with immunosuppressive therapies is associated with normalization of a skewed TCR- phenotype. The overall incidence of immunodominant T cell expansions has not been determined. The goal of our study was to assess the frequency of clonal T cell expansion in peripheral blood of MDS patients. Peripheral blood was analyzed from 52 patients for T cell CDR3-length skewing by genomic multi-plex PCR. All patients met the clinical criteria of MDS as defined by the WHO classification scheme. Patients with Refractory Anemia (RA) with and without Ringed Sideroblasts (RARS) represented 13% (n=7), Refractory Cytopenia with Multilineage Dysplasia (RCMD and RCMD-RS) represented 48% (n=25), and Refractory Anemia with Excess Blasts (RAEB1, RAEB2, and MDS that had progressed to AML) represented 38% (n=20). TCR-skewing occurred in 29 out of 52 patients with MDS (55%) compared to one out of 20 (5%) in age-matched normal controls. There was no difference in the frequency of clonal expansions based on the WHO classification. Based on the International Prognostic Scoring System (IPSS), we found that high risk patients (Int-2 and high) had a significantly higher incidence of clonal expansions than did patients with low risk disease (low and Int-1) (47% vs. 20%, respectively, p<0.05). Indeed, patients with the highest incidence of having clonal T cell expansion were in the Int-2 risk category (86% by TCR-Vβ analysis, n=7). Of 47 patients with known bone marrow cellularity classification, we enrolled only eight (17%) that were classified as hypocellular, ten (21%) normal cellular, and 29 (62%) hypercellular. No patient with a hypocellular bone marrow in our analysis showed evidence of clonal T cell expansion (p<0.05). These results suggest that clonal T cell expansion occurs prominately in high risk patients. We believe that cellular immunity in MDS could have both beneficial and deleterious effects. Antigen-specific cellular immune responses against pre-leukemic cells would be advantageous, while autoimmune destruction of normal bone marrow cells in the environment of an aggressive immune response would be deleterious. More information is needed about the role that clonal T cell expansion plays in high risk MDS.