title: Clonal B cells in Waldenström's macroglobulinemia exhibit functional features of chronic active B-cell receptor signaling.
abstract: Waldenström's macroglobulinemia (WM) is a B-cell non-Hodgkin's lymphoma (B-NHL) characterized by immunoglobulin M (IgM) monoclonal gammopathy and the medullary expansion of clonal lymphoplasmacytic cells. Neoplastic transformation has been partially attributed to hyperactive MYD88 signaling, secondary to the MYD88 L265P mutation, occurring in the majority of WM patients. Nevertheless, the presence of chronic active B-cell receptor (BCR) signaling, a feature of multiple IgM+ B-NHL, remains a subject of speculation in WM. Here, we interrogated the BCR signaling capacity of primary WM cells by utilizing multiparametric phosphoflow cytometry and found heightened basal phosphorylation of BCR-related signaling proteins, and augmented phosphoresponses on surface IgM (sIgM) crosslinking, compared with normal B cells. In support of those findings we observed high sIgM expression and loss of phosphatase activity in WM cells, which could both lead to signaling potentiation in clonal cells. Finally, led by the high-signaling heterogeneity among WM samples, we generated patient-specific phosphosignatures, which subclassified patients into a 'high' and a 'healthy-like' signaling group, with the second corresponding to patients with a more indolent clinical phenotype. These findings support the presence of chronic active BCR signaling in WM while providing a link between differential BCR signaling utilization and distinct clinical WM subgroups.
authors: Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors: K V
authors: KV
authors: Argyropoulos
authors: Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors: R
authors: R
authors: Vogel
authors: Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors: C
authors: C
authors: Ziegler
authors: Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors: G
authors: G
authors: Altan-Bonnet
authors: Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors: E
authors: E
authors: Velardi
authors: Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors: M
authors: M
authors: Calafiore
authors: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors: A
authors: A
authors: Dogan
authors: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors: M
authors: M
authors: Arcila
authors: Hematologic Oncology Tissue Bank, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors: M
authors: M
authors: Patel
authors: Hematologic Oncology Tissue Bank, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors: K
authors: K
authors: Knapp
authors: Hematologic Oncology Tissue Bank, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors: C
authors: C
authors: Mallek
authors: Bing Center for Waldenström's Macroglobulinemia, Dana Farber Cancer Institute, Boston, MA, USA.
authors: Z R
authors: ZR
authors: Hunter
authors: Bing Center for Waldenström's Macroglobulinemia, Dana Farber Cancer Institute, Boston, MA, USA.
authors: S P
authors: SP
authors: Treon
authors: Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors: M R M
authors: MR
authors: van den Brink
authors: Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors: M L
authors: ML
authors: Palomba
mesh_terms: D001402:B-Lymphocytes / Q000473:pathology*; D002999:Clone Cells / Q000473:pathology; D005260:Female; D006801:Humans; D007075:Immunoglobulin M / Q000378:metabolism; D008297:Male; D010766:Phosphorylation; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D015398:Signal Transduction; D008258:Waldenstrom Macroglobulinemia / Q000473:pathology*
chemical_list: D007075:Immunoglobulin M; D011947:Receptors, Antigen, B-Cell