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Title

The cellular origin and malignant transformation of Waldenström macroglobulinemia

AuthorsPaiva, Bruno; Corchete, Luis A.; Vidriales, Maria Belén; García-Sanz, Ramón; Pérez, José J.; Aires-Mejia, I.; Sánchez, Maria Luz; Bárcena, Paloma; Jiménez, Cristina ; Sarasquete, María Eugenia; Mateos, Maria Victoria; Ocio, Enrique M. ; Puig, Noemi; García de Coca, Alfonso; Orfao, Alberto ; Gutiérrez, Norma Carmen; San Miguel, Jesús F.
Issue Date2015
PublisherAmerican Society of Hematology
CitationBlood 125(15): 2370-2380 (2015)
AbstractAlthough 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<sup>-</sup>CD22<sup>+</sup> 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<sup>+</sup>CD22<sup>+low</sup>) 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.
URIhttp://hdl.handle.net/10261/135790
DOI10.1182/blood-2014-09-602565
Identifiersdoi: 10.1182/blood-2014-09-602565
e-issn: 1528-0020
issn: 0006-4971
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