POEMS syndrome is a rare plasma cell disorder characterized by peripheral neuropathy, monoclonal gammopathy, and high levels of serum vascular endothelial growth factor, the pathogenesis of which remains unclear. A unique feature of this syndrome is that the proliferating monoclonal plasma cells are essentially -restricted.

Dexamethasone (Dex) is an effective therapeutic agent against multiple myeloma (MM); however, resistance to it often becomes a clinical issue. CD44 is an adhesion molecule that serves as a cell surface receptor for extracellular matrix components, including hyaluronan (HA). HA is an extracellular matrix component that is involved in survival and progression in MM. In the present report, we describe isolation of a CD44-expressing population from a Dex-sensitive MM cell line, RPMI8226, in which the CD44-high population had a significantly higher potential to resist Dex than did the CD44-low population. Furthermore, we demonstrate that CD44 engagement by an anti-CD44 monoclonal antibody (mAb) or HA protects MM cells from Dex-induced growth inhibition. The activity of HA was partially inhibited by blocking its binding to CD44, indicating that CD44 mediates HA activity promoting MM cell survival. CD44 engagement by an anti-CD44 mAb led to phosphorylation and degradation of IkappaB-alpha, thus preventing its Dex-induced up-regulation. Our data suggest that CD44 is not only an important mediator for the survival activity of HA, but it may also contribute to MM cell resistance to Dex.

Weherein report a case of aceruloplasminemia in a 27-year-old man who had a 10-year history of diabetes mellitus. The patient developed a convulsion, most likely as a result of hypoglycemia. Unexpectedly, this episode left him in a prolonged state of unconsciousness, which necessitated neurological testing and imaging. Brain MRI showed bilateral hypo-intensities in the basal ganglia and thalamus. Molecular analysis revealed a novel splicing mutation in the ceruloplasmin (CP) gene that would result in the skipping of exon 3 during transcription. This case suggests that diabetes associated with aceruloplasminemia can becomemanifest in the teens. (Internal Medicine 42: 599-604, 2003)

Background: POEMS syndrome (also known as Crow-Fukase or Takatsuki syndrome) is a rare plasma cell disorder characterized by peripheral neuropathy, a monoclonal plasma cell disorder, and other paraneoplastic features including organomegaly, endocrinopathy, skin changes, edema and effusions. High levels of vascular endothelial growth factor (VEGF) in the serum may contribute to pathology seen in this disease but exact pathogenetic mechanisms are still unclear. A unique feature of this syndrome is that the proliferating monoclonal plasma cells are virtually always λ-restricted. Here, we determined complete nucleotide sequences of monoclonal immunoglobulin λ light chain (IGL) variable regions in 10 patients with POEMS syndrome and found that Vλ germline usage is highly restricted to the Vλ1 family and oligoclonal germlines. Materials and methods: Total RNA was extracted from bone marrow mononuclear cells of patients with POEMS syndrome and the V-J region of the IGL gene was amplified by RT-PCR using 5′ degenerative primers for the Vλ consensus leader lesion (5′-ATGGCCKGSWYYSYTCTCCTC-3′) and 3′ primers matching the consensus upstream part of the cl exon (5′-CTCCCGGGTAGAGAAGTCACT-3′). Monoclonal bands were detected by heteroduplex analysis or TA cloning and subjected to nucleotide sequencing. Sequence data were analyzed using the International ImMunoGeneTics information system (IMGT, http://imgt.cines.fr) and mutations were identified by comparison with the germline sequence databases. Results: Of 13 POEMS syndrome patients with λ-type M protein, nucleotide sequencing of the IGL gene was successful in 10. The V-region of the IGL gene of all 10 patients was restricted to the Vλ1 family. Searching for homologies with IGL germlines revealed that only two were used, with an average homology of 90.1%. IGLV1-40*01 was used in 8 patients and IGLV1-44*01 in the remaining two. In the IGL-J region, the IGLJ3 gene was found in 9 of 10 patients and IGLJ2 in one (10%). All IGLV-J rearrangements were mutated with homologies to the germline sequence ranging from 77.66% to 96.10% (average homology: 90.1%). All CDR3 were composed of 11 amino acids, with identical acidic isoelectric point (pI) values (13.0) and similar molecular weights ranging from 1394.7 to 1552.8 (median, 1506.2). Conclusions: IGL-M protein in POEMS syndrome belongs to the Vλ1 family and is markedly restricted to specific oligoclonal germlines. Our results suggest that the restricted use of IGL plays an important role in the pathogenesis of POEMS syndrome. These data provide an important insight for elucidating the pathogenesis of POEMS syndrome. To the best of our knowledge, this the first report of restricted oligo-clonal usage of monoclonal immunoglobulin germlines in plasma cell disorders.

Chronic myeloproliferative diseases (CMPD), a group of hematopoietic stem cell disorders often accompanied by myelofibrosis, are associated with several recently identified genetic abnormalities. However, the mechanism responsible for myelofibrosis is still unclear. TEL is an ets family transcription factor located on 12p13 which on translocation is known to form fusion genes with more than 20 partners including protein tyrosine kinases (PTK) and transcription factors. Here, we identified a novel TEL-Lyn fusion gene in chronic eosinophilic leukemia with myelofibrosis, bearing the chromosomal abnormality ins (12;8)(p13;q11q21). The patient was refractory to both imatinib therapy and allogeneic stem cell transplantation and died of blastic transformation. We established that this novel TEL-Lyn fusion gene was expressed by the patient’s peripheral blood mononuclear cells and confirmed that the TEL and Lyn genes were fused in frame at breakpoints at 1010 bp and 638 bp, respectively. This fusion gene contains the TEL PNT domain and the Lyn PTK domain. To test whether the TEL-Lyn fusion product transforms hematopoietic cells, we introduced the gene into murine IL-3 dependent Ba/F3 cells. The 75 kDa TEL-Lyn fusion protein was detected in TEL-Lyn-transfected Ba/F3 cells and found to be constitutively tyrosine-phosphorylated. TEL-Lyn-transfected Ba/F3 cells proliferated in an IL-3-independent manner, which was not blocked by imatinib but could be by dasatinib, which targets Lyn kinase. Next, we isolated CD34-c-Kit+Sca-1+lineage marker- (CD34-KSL) hematopoietic stem cells (HSCs) from C57BL/6 (B6) mouse bone marrow (BM) by FACS sorting and introduced the TEL-Lyn fusion gene using a retroviral vector. HSCs expressing TEL-Lyn formed colonies without the exogenous growth factors SCF, IL-3, EPO and TPO, which was also suppressed by dasatinib, but not imatinib. Finally, we transplanted these transfected HSCs into irradiated hosts using B6-Ly5.2 mice as recipients of TEL-Lyn or control retroviral vector-transfected HSCs from B6-Ly5.1 mice. In the TEL-Lyn group, marked neutrophillia, splenomegaly and BM fibrosis were observed. Six of 10 mice died within 6 weeks after transplantation, while all controls remained healthy over 8 weeks. Conclusions: Introduction of the TEL-Lyn fusion gene into HSCs results in rapid development of myelofibrosis as well as myeloproliferative transformation. Lyn kinase might be constitutively activated by TEL-induced oligomerization. These data imply for the first time that rearranged or activated Lyn kinase is involved in the pathogenesis of CMPD and myelofibrosis, and provide an ideal model for the latter. Further extensive study on the role of Lyn in CMPD might result in the definition of a novel clinical CMPD entity.