Distinct patterns of B-cell receptor signaling in non-Hodgkin lymphomas identified by single-cell profiling.

Myklebust JH, Brody J, Kohrt HE, Kolstad A, Czerwinski DK, Wälchli S, Green MR, Trøen G, Liestøl K, Beiske K, Houot R, Delabie J, Alizadeh AA, Irish JM, Levy R
Blood. 2017 129 (6): 759-770

PMID: 28011673 · PMCID: PMC5301824 · DOI:10.1182/blood-2016-05-718494

Kinases downstream of B-cell antigen receptor (BCR) represent attractive targets for therapy in non-Hodgkin lymphoma (NHL). As clinical responses vary, improved knowledge regarding activation and regulation of BCR signaling in individual patients is needed. Here, using phosphospecific flow cytometry to obtain malignant B-cell signaling profiles from 95 patients representing 4 types of NHL revealed a striking contrast between chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) tumors. Lymphoma cells from diffuse large B-cell lymphoma patients had high basal phosphorylation levels of most measured signaling nodes, whereas follicular lymphoma cells represented the opposite pattern with no or very low basal levels. MCL showed large interpatient variability in basal levels, and elevated levels for the phosphorylated forms of AKT, extracellular signal-regulated kinase, p38, STAT1, and STAT5 were associated with poor outcome. CLL tumors had elevated basal levels for the phosphorylated forms of BCR-signaling nodes (Src family tyrosine kinase, spleen tyrosine kinase [SYK], phospholipase Cγ), but had low α-BCR-induced signaling. This contrasted MCL tumors, where α-BCR-induced signaling was variable, but significantly potentiated as compared with the other types. Overexpression of CD79B, combined with a gating strategy whereby signaling output was directly quantified per cell as a function of CD79B levels, confirmed a direct relationship between surface CD79B, immunoglobulin M (IgM), and IgM-induced signaling levels. Furthermore, α-BCR-induced signaling strength was variable across patient samples and correlated with BCR subunit CD79B expression, but was inversely correlated with susceptibility to Bruton tyrosine kinase (BTK) and SYK inhibitors in MCL. These individual differences in BCR levels and signaling might relate to differences in therapy responses to BCR-pathway inhibitors.

© 2017 by The American Society of Hematology.

MeSH Terms (26)

Agammaglobulinaemia Tyrosine Kinase CD79 Antigens Diagnosis, Differential Flow Cytometry Gene Expression Regulation, Neoplastic Humans Immunoglobulin M Leukemia, Lymphocytic, Chronic, B-Cell Lymphoma, Follicular Lymphoma, Large B-Cell, Diffuse Lymphoma, Mantle-Cell Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 p38 Mitogen-Activated Protein Kinases Phospholipase C gamma Phosphoproteins Phosphorylation Protein-Tyrosine Kinases Proto-Oncogene Proteins c-akt Receptors, Antigen, B-Cell Signal Transduction Single-Cell Analysis src-Family Kinases STAT1 Transcription Factor STAT5 Transcription Factor Syk Kinase

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