Multiple Myeloma Presenting as Pulmonary, Gastric and Epidural Extramedullary Plasmacytomas: Synchronous Presentation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5050-5050
Author(s):  
Maged Khalil ◽  
Candice Ruby ◽  
Zili He ◽  
Shetra Sivamurthy ◽  
Steier Williams ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Extramedullary Plasmacytoma ◽  
Significant Past Medical History ◽  
Upper Airways ◽  
Response To Chemotherapy ◽  
Gastric Mass ◽  
Extramedullary Plasmacytomas

Abstract Plasma cell tumors are lymphoid neoplastic proliferations of B cells that may be classified as multiple myeloma (MM), solitary bone plasmacytoma (SBP) and extramedullary plasmacytoma (EMP). The extramedullary plasmacytoma account for 1–2% of the total number of plasma-cell growths of which 80 % are originated on the head and neck and upper airways. Males are more frequently affected at sixth-seventh decade. Herein we are presenting a case of 51 years old male with synchronous multiple extramedullary plasmacytomas involving lung, stomach and spine, Presentation of a case 51 years old black male from St. Lucia with no significant past medical history, presented to the local hospital in St. Lucia with hematemesis. Endoscopy was performed and a growth in the stomach was found. He came to the US for treatment. When seen in our hospital, patient complained of black tarry stool, severe right sided chest pain radiating to the back, generalized body aches, fatigue and 10 Lbs. weight loss within the last 2 months Physical examination: revealed tenderness on the right side of chest and back, and decreased breath sound on the righ upper lobe, otherwise unremarkable Work up including CT scan of the chest/abdomen /pelvis showed an irregular right apical mass posteriorly with destruction of the adjacent second and third ribs posteriorly and in T2 and T3 vertebrae, diffuse lytic lesions involving the spines, sacrum, ribs and sternum. There was also a large irregular soft tissue mass the posterior aspect of the fundus of the stomach. Liver, spleen and lymph nodes were normal. Laboratory studies showed WBCs 9.8, Hg 6.9, Platlets 218, BUN 71, Cr. 5.2, Ca 13.4, albumin 3.4, B2 microglobulin 7.5, TP 11.4, LDH 1063, LFT’s all normal, Cea 00 ng/ml, AFP 6.0 ng/ml, Ca19-9 9.4 U/ml, PSA.97 ng/ml, iron study, folate, B12 all within normal range, serum protein electropheresis and immunofixation showed monoclonal spike in the Gamma region 53.8% (IgG Kappa and IgA Kappa), IgG 10917 mg/dl, IgA 85 mg/dl, IgM 16 mg/dl, urine protien elctrophersis showed 88 mg/dl M-spike in beta region, 24 hours urine was 2400 mg/24 h Bone marrow biopsy showed extensive infiltration with poorly differentiated plasma cells, flow cytometry consistent with plasma cell neoplasm, cytogenetics and FISH did not show any evidence of chromosome 13 deletion or trisomy 11. Gastric mass biopsy and lung mass biopsy showed plasma cells similar to the bone marrow infiltrate consistent with plasmacytoma. Diagnosis of multiple myeloma and multiple extramedullary plasmacytomas were made. Plasmaphersis was started because of worsening renal function despite aggressive hydration. Kidney function and calcium level normalized after 5 sessions of Plasmaphersis. Chemotherapy with Doxil, Vincrestine and dexamethasone (DVd) was started. Because of the persistent drop in hemoglobin from gastric mass bleeding, Radiation therapy to the gastric area was given (2300 cGy in 4 weeks) While on treatment he developed severe bilateral lower extremities weakness, MRI showed 8 cm epidural mass at the T8 level, the field of radiation was increased to include the new lesion along with Decadron. He developed severe oral mucositis, esophagitis pancytopenia, continue to bleed from the gastric mass, and finally developed an overwhelming VRE sepsis and shock. He was transferred to MICU and expired despite aggressive supportive care. Conclusion: MM can present as multiple extramedullary plasmacytomas. The response to chemotherapy is very poor The prognosis is very poor,

Single Cell RNA-Seq Reveals Clonal Consistency and Differential Malignancy in Extramedullary Plasmacytoma of Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4808-4808
Author(s):  
Shuang Geng ◽  
Jing Wang ◽  
Mingyi Chen ◽  
Wenming Wang ◽  
Yuhong Pang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Single Cell ◽  
Plasma Cell ◽  
Peripheral Blood ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Extramedullary Plasmacytoma ◽  
Rna Seq ◽  
Malignant Plasma Cell

Abstract Extramedullary Plasmacytoma (EMP) is a minor yet devastating metastatic form of Multiple Myeloma (MM), shortening patients' survival from 10 years to 6 months on average. Genetic cause of EMP in MM is yet to be defined. Transcriptome difference between EMP+ patients and EMP- patients is studied here on single cell level by RNA Sequencing (RNA-Seq). We sorted CD38+CD138+ malignant plasma cells from bone marrow and peripheral blood samples by flow cytometry, then picked up single malignant plasma cell and performed single cell RNA-Seq with SmartSeq2 protocol followed by Tn5-based library preparation from bone marrow, peripheral blood and extramedullary tissue of EMP patients. From the single cell RNA-Seq results, in bone marrow we found differential gene expression between EMP+ and EMP- samples, such as CTAG2, STMN1 and RRM2. By comparing circulating malignant plasma cells in PBMC and malignant plasma cell from the sample EMP+ patient, we observed metastatic clone in blood with the same VDJ immunoglobulin heavy chain as in bone marrow. Several genes' expression of these metastatic cells are down-regulated than in bone marrow, such as PAGE2, GTSF1, DICER1. These genes may correlate with egress capability of MM cells into peripheral to become circulating plasma cells (cPCs), and EMP eventually. Disclosures No relevant conflicts of interest to declare.

scholarly journals Multiple myeloma: circulating lymphocytes that express plasma cell antigens

Blood ◽  
1984 ◽  
Vol 64 (2) ◽  
pp. 352-356
Author(s):  
GJ Ruiz-Arguelles ◽  
JA Katzmann ◽  
PR Greipp ◽  
NJ Gonchoroff ◽  
JP Garton ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Peripheral Blood ◽  
Plasma Cells ◽  
Peripheral Blood Lymphocytes ◽  
Tumor Burden ◽  
B Cell Differentiation ◽  
Blood Lymphocytes ◽  
Bone Marrow Plasma

The bone marrow and peripheral blood of 14 patients with multiple myeloma were studied with murine monoclonal antibodies that identify antigens on plasma cells (R1–3 and OKT10). Peripheral blood lymphocytes expressing plasma cell antigens were found in six cases. Five of these cases expressed the same antigens that were present on the plasma cells in the bone marrow. Patients that showed such peripheral blood involvement were found to have a larger tumor burden and higher bone marrow plasma cell proliferative activity. In some patients, antigens normally found at earlier stages of B cell differentiation (B1, B2, and J5) were expressed by peripheral blood lymphocytes and/or bone marrow plasma cells.

scholarly journals Myeloma Cell Associated Therapeutic Protein Discovery Using Single Cell RNA-Seq Data

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 4-5
Author(s):  
Lijun Yao ◽  
Reyka G Jayasinghe ◽  
Tianjiao Wang ◽  
Julie O'Neal ◽  
Ruiyang Liu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Surface ◽  
B Cell ◽  
Tumor Cells ◽  
Plasma Cell ◽  
Tissue Specificity ◽  
Plasma Cells ◽  
Expression Data ◽  
Intracellular Proteins

Multiple myeloma (MM) is a hematological cancer of the antibody-secreting plasma cells. Despite therapeutic advancements, MM remains incurable due to high incidence of drug-resistant relapse. In recent years, targeted immunotherapies, which take advantage of the immune system's cytotoxic defenses to specifically eliminate tumor cells expressing certain cell surface and intracellular proteins have shown promise in combating this and other B cell hematologic malignancies. A major limitation in the development of these therapies lies in the discovery of optimal candidate targets, which require both high expression in tumor cells as well as stringent tissue specificity. In an effort to identify potential myeloma-specific target antigens, we performed an unbiased search for genes with specific expression in plasma and/or B cells using single-cell RNA-sequencing (scRNAseq) of 53 bone marrow samples taken from 42 patients. By comparing >40K plasma cells to >97K immune cells across our cohort, we were able to identify a total of 181 plasma cell-associated genes, including 65 that encode cell-surface proteins and 116 encoding intracellular proteins. Of particular interest is that the plasma cells from each patient were shown to be transcriptionally distinct with unique sets of genes expressed defining each patient's malignant plasma cells. Using pathway enrichment analysis, we found significant overrepresentation of cellular processes related to B-Cell receptor (BCR) signaling, protein transport, and endoplasmic reticulum (ER) stress, involving genes such as DERL3, HERPUD1, PDIA4, PDIA6, RRBP1, SSR3, SSR4, TXNDC5, and UBE2J1. To note, our strategy successfully captured several of the most promising MM therapeutic targets currently under pre-clinical and clinical trials, including TNFRSF17(BCMA), SLAMF7, and SDC1 (CD138). Among these, TNFRSF17 showed very high plasma cell expression, with concomitant sharp exclusion of other immune cell types. To ascertain tissue specificity of candidate genes outside of the bone marrow, we analyzed gene and protein expression data from the Genotype-Tissue Expression (GTEx) portal and Human Protein Atlas (HPA). We found further support for several candidates (incl. TNFRSF17,SLAMF7, TNFRSF13B (TACI), and TNFRSF13C) as being both exclusively and highly expressed in lymphoid tissues. While several surface candidates were not found to be lymphocyte-restricted at the protein level, they remain relevant considerations as secondary targets for bi-specific immunotherapy approaches currently under development. To further investigate potential combinatorial targeting, we examine sample-level patterns of candidate co-expression and mutually-exclusive expression using correlation analysis. As the majority of our detected plasma cell-specific genes encode intracellular proteins, we investigated the potential utility of these epitopes as therapeutic targets via MHC presentation. Highly expressed candidates include MZB1, SEC11C, HLA-DOB, POU2AF1, and EAF2. We analyzed protein sequences using NetMHC and NETMHCII to predict high-affinity peptides for common class-I and class-II HLA alleles. To correlate MHC allelic preference with candidate expression in our cohort, we performed HLA-typing for 29 samples using Optitype. To support our scRNAseq-driven findings, we cross-referenced gene expression data with 907 bulk RNA-sequencing samples, including 15 from internal studies and 892 from the Multiple Myeloma Research Foundation (MMRF), as well as bulk global proteomics data from 4 MM cell lines (TIB.U266, RPMI8226, OPM2, MM1ST) and 4 patients. We see consistent trends across both cohorts, with high positive correlation (Pearson R ranging between 0.60 and 0.99) for a majority of genes when comparing scRNA and bulk RNA expression in the same samples. Our experimental design and analysis strategies enabled the efficient discovery of myeloma-associated therapeutic target candidates. In conclusion, this study identified a set of promising myeloma CAR-T targets, providing novel treatment options for myeloma patients. Disclosures Goldsmith: Wugen Inc.: Consultancy. DiPersio:Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Primary Plasmacytoma of the Breast

2001 ◽  
Vol 125 (8) ◽  
pp. 1078-1080 ◽  
Author(s):  
Annarosaria De Chiara ◽  
Simona Losito ◽  
Luigi Terracciano ◽  
Raimondo Di Giacomo ◽  
Giancarla Iaccarino ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Differential Diagnosis ◽  
Correct Diagnosis ◽  
Extramedullary Plasmacytoma ◽  
Frozen Sections ◽  
Solitary Extramedullary Plasmacytoma ◽  
Extramedullary Plasmacytomas

Abstract We describe a solitary extramedullary plasmacytoma of the breast in a 37-year-old woman. No other involvement was detected in the bone marrow or in any other site during a 15-month follow-up period. Extramedullary plasmacytomas of the breast are extremely rare, especially those that are not associated with multiple myeloma. We review the histologic features of the previously reported cases with an emphasis on differential diagnosis and the difficulties encountered in arriving at the correct diagnosis in frozen sections.

scholarly journals THE BONE MARROW ON STERNAL ASPIRATION IN MULTIPLE MYELOMA

Blood ◽  
1948 ◽  
Vol 3 (9) ◽  
pp. 987-1018 ◽  
Author(s):  
EDWIN D. BAYRD
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Myeloma Cell ◽  
Multinucleated Cells ◽  
Cytoplasmic Bodies ◽  
Plasma Cell Type ◽  
Well Differentiated ◽  
Diagnostic Pitfalls

Abstract Generalizing, it can be said that the pathologic cells seen in smears of the bone marrow in multiple myeloma resemble the plasma cell and vary from the very anaplastic and immature cell to the well-differentiated and almost characteristic plasma cell. The feature which the "myeloma" cell shares with the plasma cell is the abundant, granular, basophilic cytoplasm which tends to be fragile and undergo the same degenerative changes in each; namely, the formation of Russell bodies and vacuolization. Fairly frequently a perinuclear clear area or Hof is present and the nucleus tends to be eccentrically placed. Cytoplasmic extensions or pseudopodia may also be seen in either case, but they occur more often and more dramatically in instances of multiple myeloma. Multinucleated cells are commonly seen. In addition, myeloma-plasma cells will often have a large clear nucleolus and a leptochromatic nucleus and will exhibit a tendency to the formation of isolated areas of condensed chromatin. Cytoplasmic extrusions, free cytoplasmic bodies, occasionally complete with Russell bodies and vacuoles are almost universally present. All cases were of the plasma cell type; there was no exception. In these cases, the myeloma-plasma cell constituted from 2.5 to 96 per cent of the leukocytic elements present. The opinion was expressed that all so-called types of multiple myeloma are merely variations in differentiation of this same cell. It was noted that anaplasia, hypernucleation and lack of plasma cell predominance in certain cases were diagnostic pitfalls. Additional evidence was adduced to confirm the reticulo-endothelial origin of the myeloma-plasma cell. It was further observed that certain prognostically valuable information could be gleaned from a careful review of the cytologic characteristics in these cases.

scholarly journals Rare Presentation of Primary Extramedullary Plasmacytoma as Lip Lesion

2017 ◽  
Vol 2017 ◽  
pp. 1-5
Author(s):  
Mali Him ◽  
Maggie Meier ◽  
Vikas Mehta
Keyword(s):  
Multiple Myeloma ◽  
Cell Proliferation ◽  
Plasma Cell ◽  
Light Chain ◽  
Extramedullary Plasmacytoma ◽  
Solitary Plasmacytoma ◽  
Rare Presentation ◽  
Lower Lip ◽  
Light Chain Disease ◽  
Extramedullary Plasmacytomas

Malignant plasma cell proliferation can be presented as part of disseminated disease of multiple myeloma, as solitary plasmacytoma of bone, or in soft tissue as extramedullary plasmacytoma. Extramedullary plasmacytomas represented approximately 3% of all plasma cell proliferation. Approximately 80% of extramedullary plasmacytomas occur in the head and neck region while the other 4% occur in the skin and to a lesser extent in the lip. In this paper, we report a rare case of primary cutaneous plasmacytoma involving the lip in a 65-year-old male. The patient presented with a nonhealing lower lip sore for the past 3 years. Upon further workup, there was no evidence of multiple myeloma or light chain disease. The patient was treated with radiation therapy and his last follow-up revealed no evidence of multiple myeloma or light chain disease.

scholarly journals Extramedullary plasmacytoma of the tongue: A case report

2021 ◽  
Vol 2 (6) ◽  
Author(s):  
Leart Berdica ◽  
◽  
Teona Bushati ◽  
Alfred Aga ◽  
Emirjona Vajushi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Differential Diagnosis ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Histopathological Examination ◽  
English Literature ◽  
Extramedullary Plasmacytoma ◽  
Imaging Data ◽  
Plasma Cell Neoplasms ◽  
Extramedullary Plasmocytoma

Background: Tongue extramedullary plasmacytoma is a very rare pathology. Despite rare cases, extramedullary plasmacytoma should be considered as a differential diagnosis in case of a mass in the tongue. A total of 19 cases were reported with EMP in English literature along with the case we will address. It is characterized by a monoclonal neoplastic proliferation of plasma cells in the absence of multiple myeloma (MM). Histopathology and immunohistochemistry are very important for the diagnosis and differential diagnosis. Case presentation: The case we will describe is an 80-year-old lady from Albania who presents with a vegetative lesion in the form of a thick plate on the dorsal part of the tongue with dimensions 6 X 5 X 1.5 cm. A material of 0.5 cm diameter was taken from the lesion for the biopsy. After histopathological examination, immunohistochemical examinations, and after correlations with laboratory, clinical and imaging data, the diagnosis of extramedullary plasmacytoma of the tongue was reached. The patient underwent radiotherapy treatment. Conclusions: EMP is a rare tumor, accounting for 3% of plasma cell neoplasms and <1% of all head and neck tumors. The diagnosis of EMP, in this case, was reached with biopsy, immunohistochemistry, and the correlation with laboratory and imaging data. We will show the importance of biopsy along with immunohistochemistry in the diagnosis and differential diagnosis of extramedullary plasmocytoma of the tongue. Keywords: plasmacytoma; immunohistochemistry; biopsy; plasma cell. Abbreviations: EMP: Extramedullary plasmacytoma; MM: Multiple myeloma; Cm: centimeter

scholarly journals Salmonella SiiE prevents an efficient humoral immune memory by interfering with IgG+ plasma cell persistence in the bone marrow

2019 ◽  
Vol 116 (15) ◽  
pp. 7425-7430 ◽  
Author(s):  
Christian Männe ◽  
Akiko Takaya ◽  
Yuzuru Yamasaki ◽  
Mathias Mursell ◽  
Shintaro Hojyo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Autoimmune Diseases ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Therapeutic Option ◽  
Immune Memory ◽  
Humoral Immune ◽  
Serum Igg ◽  
Specific Igg

Serum IgG, which is mainly generated from IgG-secreting plasma cells in the bone marrow (BM), protects our body against various pathogens. We show here that the protein SiiE of Salmonella is both required and sufficient to prevent an efficient humoral immune memory against the pathogen by selectively reducing the number of IgG-secreting plasma cells in the BM. Attenuated SiiE-deficient Salmonella induces high and lasting titers of specific and protective Salmonella-specific IgG and qualifies as an efficient vaccine against Salmonella. A SiiE-derived peptide with homology to laminin β1 is sufficient to ablate IgG-secreting plasma cells from the BM, identifying laminin β1 as a component of niches for IgG-secreting plasma cells in the BM, and furthermore, qualifies it as a unique therapeutic option to selectively ablate IgG-secreting plasma cells in autoimmune diseases and multiple myeloma.

The Natural History of Smoldering (Asymptomatic) Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3396-3396 ◽  
Author(s):  
Robert Kyle ◽  
Ellen Remstein ◽  
Terry Therneau ◽  
Angela Dispenzieri ◽  
Paul Kurtin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Light Chain ◽  
Plasma Cells ◽  
M Protein ◽  
Cell Content ◽  
Bone Marrow Plasma ◽  
M Spike

Abstract Smoldering multiple myeloma (SMM) is characterized by a serum M protein ≥ 3g/dL and/or 10% or more of plasma cells in the bone marrow. However, the definition is not standardized, and it is not known whether both serum M protein levels and bone marrow plasma cell counts are necessary for diagnosis or if one parameter is sufficient. We reviewed the medical records and bone marrows of all patients from Mayo Clinic seen within 30 days of recognition of an IgG or IgA M protein ≥ 3g/dL or a bone marrow containing ≥ 10% plasma cells from 1970 to 1995. This allows for a minimum potential follow-up of 10 years. Patients with end-organ damage at baseline from plasma cell proliferation, including active multiple myeloma (MM) and primary amyloidosis (AL) and those who had received chemotherapy were excluded. A differential of the bone marrow aspirate coupled with the bone marrow biopsy morphology and immunohistochemistry using antibodies directed against CD138, MUM-1 and Cyclin D1 were evaluated in every case in order to estimate the plasma cell content. In all, 301 patients fulfilled either of the criteria for SMM. Their median age was 64 years and only 3% were less than 40 years of age; 60% were male. The median hemoglobin value was 12.9 g/dL; 7% were less than 10 g/dL, but the anemia was unrelated to plasma cell proliferation. IgG accounted for 75%, IgA 22%, and biclonal proteins were found in 3%. The serum light-chain was κ in 67% and λ in 33%. The median serum M spike was 2.9 g/dL; 11% were at least 4.0 g/dL. Uninvolved serum immunoglobulins were reduced in 81%; only 1 immunoglobulin was reduced in 31% and both were decreased in 50%. The urine contained a monoclonal κ protein in 36% and λ in 18% and 46% were negative. The median size of the urine M spike was 0.04 g/24h; only 5 (3%) were &gt; 1 g/24h. The median bone marrow plasma cell content was 15 – 19%; 10% had less than 10% plasma cells, while 10% had at least 50% plasma cells in the bone marrow. Cyclin D-1 was expressed in 17%. Patients were categorized into 3 groups: Group 1, serum M protein ≥ 3g/dL and bone marrow containing ≥ 10% plasma cells (n= 113, 38%); Group 2, bone marrow plasma cells ≥ 10% but serum M protein &lt; 3g/dL (n= 158, 52%); Group 3, serum M protein ≥ 3g/dL but bone marrow plasma cells &lt; 10% (n= 30, 10%). During 2,204 cumulative years of follow-up 85% died (median follow-up of those still living 10.8 years), 155 (51%) developed MM, while 7 (2%) developed AL. The overall rate of progression at 10 years was 62%; median time to progression was 5.5 yrs. The median time to progression was 2.4, 9.2, and 19 years in groups 1, 2, and 3 respectively; correspondingly at 10 years, progression occurred in 76%, 59%, and 32% respectively. Significant risk factors for progression with univariate analysis were serum M spike ≥ 4g/dL (p &lt; 0.001), presence of IgA (p = 0.003), presence of urine light chain (p = 0.006), presence of λ urinary light chain (p = 0.002), bone marrow plasma cells ≥ 20% (p &lt; 0.001) and reduction of uninvolved immunoglobulins (p &lt; 0.001). The hemoglobin value, gender, serum albumin, and expression of cyclin D-1 were not of prognostic importance. On multivariate analysis, the percentage of bone marrow plasma cells was the only significant factor predicting progression to MM or AL.

Angiogenesis in Multiple Myeloma (MM): Angiogenic Switch or Reflexion of Plasma Cell Number? A Gene Expression Based Survey in Primary Myeloma Cells and the Bone Marrow Microenvironment.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3405-3405
Author(s):  
Dirk Hose ◽  
John DeVos ◽  
Christiane Heiß ◽  
Jean-Francois Rossi ◽  
Angela Rösen-Wolff ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Empirical Bayes ◽  
Plasma Cells ◽  
De Novo ◽  
Cell Number ◽  
Bone Marrow Microenvironment ◽  
Myeloma Cells ◽  
Angiogenic Switch

Abstract BACKGROUND. Angiogenesis is a hallmark of active multiple myeloma. However, two etiologic hypotheses have been proposed: an angiogenic switch (i.e. differential or de novo expression of pro/antiangiogenic genes in MM), and, alternatively an effect of increased plasma cell number. AIM of this study was to investigate the angiogenic signature of multiple myeloma cells (MMC), normal bone marrow plasma cells (BMPC), the bone marrow microenvironment (BMME) and cellular subfractions therein. PATIENTS AND METHODS. 128 newly diagnosed MM-patients (65 training (TG) / 63 independent validation group (VG)) and 14 normal donors (ND) were included. Bone marrow aspirates were CD138-purified by activated magnetic cell sorting. Whole bone marrow (n=49) and FACSAria sorted subfractions thereof (n=5) were investigated. RNA was in-vitro transcribed and hybridised to Affymetrix HG U133 A+B GeneChip (TG) and HG U133 2.0 plus arrays (VG). Expression data were gcrma-normalised and the empirical Bayes algorithm used. p-Values were adjusted using the Benjamini-Hochberg method (Bioconductor). iFISH was performed on purified MM-cells using probesets for chromosomes 1q21, 9q34, 11q23, 11q13, 13q14, 15q22, 17p13, 19q13, 22q11 and the translocations t(4;14) and t(11;14). HGF expression was verified by real time RT-PCR and western blotting. Based on Medline review, we established a list of 89 pro- and 56 antiangiogenic genes and investigated their expression according to the stage of disease: BMPC vs. MGUS, SD stage I (asymptomatic myeloma) vs. SD stage II/III (symptomatic myeloma requiring therapy). RESULTS. BMPC express pro- (e.g. VEGFA) and antiangiogenic genes (e.g. TIMP2). Only one pro-angiogenic gene (hepatocyte growth factor, HGF) is significantly overexpressed in MMC compared to BMPC. HGF has previously been linked with myeloma progression and induction of angiogenesis. Six antiangiogenic genes (TIMP2, SERPINF1, COL18A1, PF4, THBS1, CXCL14) are downregulated in MMC compared with BMPC. Compared to healthy donors, the BMME of MM shows a significant downregulation of PLAU (urokinase, antiangiogenic) and upregulation of TNF(proangiogenic). CONCLUSION. Upregulation of HGF-expression, downregulation of TIMP2, SERPINF1, COLA18A1, PF4, THBS1 and CXCL14 expression in MMC as well as downregulation of PLAU and upregulation of TNFα in the BMME seem to indicate an “angiogenic switch”. However, given the relatively low number of differentially expressed genes (7/145) and the expression of angiogenic genes by BMPC, an effect caused by an increasing number of plasma cells might be evenly important.

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