title: The cellular origin and malignant transformation of Waldenström macroglobulinemia.
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.
authors: Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain;
authors: Bruno
authors: B
authors: Paiva
authors: Hospital Universitario de Salamanca, Instituto de Investigaion Biomedica de Salamanca, Centro de Investigación del Cancer (IBMCC-USAL, CSIC), Salamanca, Spain;
authors: Luis A
authors: LA
authors: Corchete
authors: Hospital Universitario de Salamanca, Instituto de Investigaion Biomedica de Salamanca, Centro de Investigación del Cancer (IBMCC-USAL, CSIC), Salamanca, Spain;
authors: Maria-Belen
authors: MB
authors: Vidriales
authors: Hospital Universitario de Salamanca, Instituto de Investigaion Biomedica de Salamanca, Centro de Investigación del Cancer (IBMCC-USAL, CSIC), Salamanca, Spain;
authors: Ramón
authors: R
authors: García-Sanz
authors: Hospital Universitario de Salamanca, Instituto de Investigaion Biomedica de Salamanca, Centro de Investigación del Cancer (IBMCC-USAL, CSIC), Salamanca, Spain;
authors: Jose J
authors: JJ
authors: Perez
authors: Hospital Universitario de Salamanca, Instituto de Investigaion Biomedica de Salamanca, Centro de Investigación del Cancer (IBMCC-USAL, CSIC), Salamanca, Spain;
authors: Irene
authors: I
authors: Aires-Mejia
authors: Servicio General de Citometría and Department of Medicine, Universidad de Salamanca, Salamanca, Spain;
authors: Maria-Luz
authors: ML
authors: Sanchez
authors: Servicio General de Citometría and Department of Medicine, Universidad de Salamanca, Salamanca, Spain;
authors: Paloma
authors: P
authors: Barcena
authors: Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain;
authors: Diego
authors: D
authors: Alignani
authors: Hospital Universitario de Salamanca, Instituto de Investigaion Biomedica de Salamanca, Centro de Investigación del Cancer (IBMCC-USAL, CSIC), Salamanca, Spain;
authors: Cristina
authors: C
authors: Jimenez
authors: Hospital Universitario de Salamanca, Instituto de Investigaion Biomedica de Salamanca, Centro de Investigación del Cancer (IBMCC-USAL, CSIC), Salamanca, Spain;
authors: Maria-Eugenia
authors: ME
authors: Sarasquete
authors: Hospital Universitario de Salamanca, Instituto de Investigaion Biomedica de Salamanca, Centro de Investigación del Cancer (IBMCC-USAL, CSIC), Salamanca, Spain;
authors: María-Victoria
authors: MV
authors: Mateos
authors: Hospital Universitario de Salamanca, Instituto de Investigaion Biomedica de Salamanca, Centro de Investigación del Cancer (IBMCC-USAL, CSIC), Salamanca, Spain;
authors: Enrique M
authors: EM
authors: Ocio
authors: Hospital Universitario de Salamanca, Instituto de Investigaion Biomedica de Salamanca, Centro de Investigación del Cancer (IBMCC-USAL, CSIC), Salamanca, Spain;
authors: Noemi
authors: N
authors: Puig
authors: Complejo Hospitalario de León, León, Spain;
authors: Fernando
authors: F
authors: Escalante
authors: Hospital General de Segovia, Segovia, Spain;
authors: José
authors: J
authors: Hernández
authors: Hospital Clínico Universitario de Valladolid, Valladolid, Spain;
authors: Rebeca
authors: R
authors: Cuello
authors: Hospital Clínico Universitario de Valladolid, Valladolid, Spain;
authors: Alfonso
authors: A
authors: García de Coca
authors: Hospital Virgen de la Concha, Zamora, Spain;
authors: Magdalena
authors: M
authors: Sierra
authors: Hospital Virgen de la Concha, Zamora, Spain;
authors: Maria-Carmen
authors: MC
authors: Montes
authors: Hospital Universitario de Burgos, Burgos, Spain;
authors: Tomás J
authors: TJ
authors: González-López
authors: Hospital Comarcal del Bierzo, Ponferrada, Spain;
authors: Josefina
authors: J
authors: Galende
authors: Hospital Nuestra Señora de Sonsoles, Ávila, Spain;
authors: Abelardo
authors: A
authors: Bárez
authors: Hospital Rio Carrión, Palencia, Spain; and.
authors: José
authors: J
authors: Alonso
authors: Hospital Virgen del Puerto, Plasencia, Spain.
authors: Emilia
authors: E
authors: Pardal
authors: Servicio General de Citometría and Department of Medicine, Universidad de Salamanca, Salamanca, Spain;
authors: Alberto
authors: A
authors: Orfao
authors: Hospital Universitario de Salamanca, Instituto de Investigaion Biomedica de Salamanca, Centro de Investigación del Cancer (IBMCC-USAL, CSIC), Salamanca, Spain;
authors: Norma C
authors: NC
authors: Gutierrez
authors: Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain;
authors: Jesús F
authors: JF
authors: San Miguel
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D002999:Clone Cells; D005434:Flow Cytometry; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D006801:Humans; D007075:Immunoglobulin M / Q000032:analysis; D008998:Monoclonal Gammopathy of Undetermined Significance / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D010641:Phenotype; D008258:Waldenstrom Macroglobulinemia / Q000235:genetics* / Q000473:pathology
chemical_list: D007075:Immunoglobulin M; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88