The cellular origin and malignant transformation of Waldenstrm's Macroglobulinemia [gene expression]

Although information on the molecular pathogenesis of Waldenstrms Macroglobulinemia (WM) has greatly improved in recent years, the exact cellular origin and the mechanisms behind WM transformation from IgM 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=17), and symptomatic WM (n=10). Through principal-component-analysis of multidimensional flow cytometry data, we demonstrated overlapping phenotypic profiles between clonal B-cells from IgM MGUS, smoldering and symptomatic WM patients. Similarly, virtually no genes were significantly deregulated between FACS-sorted clonal B-cells from the three disease stages. Interestingly, while the transcriptome of the Waldenstrms clone was highly deregulated as compared to CD25-CD22+ normal B-cells, significantly less genes were differentially expressed and specific WM pathways down-regulated while comparing the transcriptome of the Waldenstrms clone vs. its normal phenotypic counterpart: CD25+CD22+dim B-cells. 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 (i.e.: IgM MGUS and smoldering WM), already harbor the phenotypic and molecular signatures of the malignant Waldenstrms clone.

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Paiva B, Corchete LA, Vidriales MB, García-Sanz R, Perez JJ, Aires-Mejia I, Sanchez ML, Barcena P, Alignani D, Jimenez C, Sarasquete ME, Mateos MV, Ocio EM, Puig N, Escalante F, Hernández J, Cuello R, García de Coca A, Sierra M, Montes MC, González-López TJ, Galende J, Bárez A, Alonso J, Pardal E, Orfao A, Gutierrez NC, San Miguel JF