Clonal B cells in Waldenstrom's macroglobulinemia exhibit functional features of chronic active B-cell receptor signaling Journal Article

   

Authors:	Argyropoulos, K. V.; Vogel, R.; Ziegler, C.; Altan-Bonnet, G.; Velardi, E.; Calafiore, M.; Dogan, A.; Arcila, M.; Patel, M.; Knapp, K.; Mallek, C.; Hunter, Z. R.; Treon, S. P.; van den Brink, M. R. M.; Palomba, M. L.
Article Title:	Clonal B cells in Waldenstrom's macroglobulinemia exhibit functional features of chronic active B-cell receptor signaling
Abstract:	Waldenstrom'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.
Keywords:	somatic mutation; tyrosine kinase; follicular lymphoma; acute lymphoblastic-leukemia; tumor progression; chronic lymphocytic-leukemia; non-hodgkin-lymphoma; flow-cytometry; gammopathy; myd88 l265p; m monoclonal
Journal Title:	Leukemia
Volume:	30
Issue:	5
ISSN:	0887-6924
Publisher:	Nature Publishing Group
Date Published:	2016-05-01
Start Page:	1116
End Page:	1125
Language:	English
ACCESSION:	WOS:000375691800013
DOI:	10.1038/leu.2016.8
PROVIDER:	wos
PMCID:	PMC4858584
PUBMED:	26867669
Notes:	Article -- Source: Wos

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