The cellular origin and malignant transformation of Waldenström macroglobulinemia.

Bruno Paiva, Luis A Corchete, Maria-Belen Vidriales, Ramón García-Sanz, Jose J Perez, Irene Aires-Mejia, Maria-Luz Sanchez, Paloma Barcena, Diego Alignani, Cristina Jimenez, Maria-Eugenia Sarasquete, María-Victoria Mateos, Enrique M Ocio, Noemi Puig, Fernando Escalante, José Hernández, Rebeca Cuello, Alfonso García de Coca, Magdalena Sierra, Maria-Carmen Montes, Tomás J González-López, Josefina Galende, Abelardo Bárez, José Alonso, Emilia Pardal, Alberto Orfao, Norma C Gutierrez, Jesús F San Miguel

Index: Blood 125 , 2370-80, (2015)

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Abstract

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. © 2015 by The American Society of Hematology.