Study Germline Light Chain Variable Region Gene Expression In Restricted λ POEMS Syndrome

Background:POEMS syndrome is a rare plasma cell dyscrasia characterized by polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes. The pathogenesis of POEMS syndrome is not fully understood. Recent studies have revealed that the IGLV genes in patients with POEMS syndrome all belong to Vλ1subfamily, and the germline genes are either IGLV1-40or IGLV1-44specifically. Although these studies were based on small samples of patients, they have given great insights to our understanding of the roles M protein and λ light chains have played in the pathogenesis of POEMS syndrome.Objective:1. To amplify and analyze the sequence of IGLV genes in patients with POEMS syndrome, and compare the results with IGLV germline gene sequence;2. To evaluate serum angiogenesis cytokines levels in patients with POEMS syndrome;3. To compare patients with different IGLV germline genes, to find out whether there lies difference in their clinical characteristics, M protein, or serum cytokine levels.Methods:Total RNA from bone marrow mononuclear cells of patients with POEMS syndrome were extracted, based on which single-strand cDNA was synthesized. IGLV genes were amplified and sequenced, and their germline gene types were determined according to IMGT database. Mutations and patients’ clinical characteristics were further analyzed; also serum angiogenesis cytokines levels were measured by ELISA assay.Results:1. We have successfully amplified and analyzed IGLV genes in30patients with POEMS syndrome. After compared with gemline gene sequence, the IGLV germline genes in11of30patients with POEMS syndrome were IGLV1-40(with median homology at94.10%),19of those germline genes were IGLV1-44(median homology was92.28%). Therefore, the usage of IGLV genes in POEMS syndrome is germline restricted. Further analyze found out the ratio of replacement mutations (R) to silent mutations (S) in the complementarity determining regions was higher than that in the framework regions, suggesting the clonal plasma cells in patients with POEMS syndrome have undergone antigen selection.2. There have been no differences in clinical characteristics such as age, gender, neuropathy, organmegaly, Castleman’s disease, endocrinopathy, M protein, edema, extravascular volume overload, lung disease, bone lesions and renal impairment between POEMS syndrome patients with different IGLV genes. Neither have there been differences in hemoglobin and platelet count or serum VEGF level. However, POEMS syndrome patients with IGLV1-40or IGLV1-44differ in papilledema and hypertrichosis,(p value equals to0.023and0.014, respectively).3. Mean serum VEGF level in patients with POEMS syndrome was4061±643pg/ml (expressed as mean±standard error), and mean serum VEGF levels in10patients with multiple myeloma and10health persons were1806±758pg/ml and425±100pg/ml respectively. Serum VEGF levels in patients with POEMS syndrome were increased than those in patients with multiple myeloma (p=0.021) or normal people (p<0.0001).4. Compared with patients with low levels of serum VEGF, patients with higher levels of serum VEGF had developed more severe neuropathy, and were more susceptible to lymphadenopathy and pulmonary hypertension. Patients with higher levels of serum VEGF also had less creatinine clearance rate and hemoglobin count, and had prolonged PT and APTT.Conclusion:1. IGLV genes in patients with POEMS syndrome are gemline genes restricted, which are IGLV1-40and IGLV1-44, and these IGLV genes have undergone antigen selection.2. Patients with IGLV1-40germline gene are more susceptible to papilledema and hypertrichosis than those with IGLV1-44germline gene.3. Serum VEGF levels in patients with POEMS syndrome are significantly increased.4. There are different clinical characteristics between patients with different levels of serum VEGF, suggesting VEGF has an important role in the pathogenesis of POEMS syndrome.