The cellular origin and malignant transformation of Waldenström macroglobulinemia
| Autor: | Josefina Galende, Paloma Bárcena, Diego Alignani, Alfonso García de Coca, Maria-Luz Sanchez, Noemi Puig, Rebeca Cuello, Alberto Orfao, Maria-Victoria Mateos, Luis A. Corchete, María-Belén Vidriales, José L. Alonso, Abelardo Bárez, Bruno Paiva, Cristina Jimenez, Irene Aires-Mejia, Maria-Carmen Montes, Norma C. Gutiérrez, Ramón García-Sanz, Tomás José González-López, José Augusto Evangelho Hernandez, M. E. Sarasquete, Jesús F. San Miguel, Enrique M. Ocio, Fernando Escalante, Magdalena Sierra, José de Jesús Pérez, Emilia Pardal |
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| Přispěvatelé: | Red Temática de Investigación Cooperativa en Cáncer (España), Junta de Castilla y León |
| Rok vydání: | 2015 |
| Předmět: |
Immunology
Gene Dosage Monoclonal Gammopathy of Undetermined Significance Biochemistry Malignant transformation Transcriptome hemic and lymphatic diseases medicine Humans IL-2 receptor B-Lymphocytes biology Waldenstrom macroglobulinemia Genomics Cell Biology Hematology Flow Cytometry medicine.disease Molecular biology Clone Cells Gene Expression Regulation Neoplastic Cell Transformation Neoplastic Phenotype Immunoglobulin M Mutation Myeloid Differentiation Factor 88 biology.protein Waldenstrom Macroglobulinemia Antibody Clone (B-cell biology) Monoclonal gammopathy of undetermined significance |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2014-09-602565 |
| Popis: | Although information about the molecular pathogenesis of Waldenström macroglobulinemia (WM) has significantly advanced, the precise cell of origin and the mechanisms behind WM transformation from immunoglobulin-M (IgM) monoclonal gammopathy of undetermined significance (MGUS) remain undetermined. Here, we undertook an integrative phenotypic, molecular, and genomic approach to study clonal B cells from newly diagnosed patients with IgM MGUS (n = 22), smoldering (n = 16), and symptomatic WM (n = 11). Through principal component analysis of multidimensional flow cytometry data, we demonstrated highly overlapping phenotypic profiles for clonal B cells from IgM MGUS, smoldering, and symptomatic WM patients. Similarly, virtually no genes were significantly deregulated between fluorescence-activated cell sorter-sorted clonal B cells from the 3 disease groups. Interestingly, the transcriptome of the Waldenström B-cell clone was highly different than that of normal CD25-CD22+ B cells, whereas significantly less genes were differentially expressed and specific WM pathways normalized once the transcriptome of the Waldenström B-cell clone was compared with its normal phenotypic (CD25+CD22+low) B-cell counterpart. The frequency of specific copy number abnormalities [+4, del(6q23.3-6q25.3), +12, and +18q11-18q23] progressively increased from IgM MGUS and smoldering WM vs symptomatic WM (18% vs 20% and 73%, respectively; P = .008), suggesting a multistep transformation of clonal B cells that, albeit benign (ie, IgM MGUS and smoldering WM), already harbor the phenotypic and molecular signatures of the malignant Waldenström clone. This study was supported by Cooperative Research Thematic Network grants RD12/0036/0058 and RD12/0036/0048 of the Red de Cancer (Cancer Network of Excellence), Consejería de Sanidad, Junta de Castilla y Leon, Valladolid, Spain (557/A/10). |
| Databáze: | OpenAIRE |
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