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

June H. Myklebust, Joshua Brody, Holbrook E. Kohrt, Arne Kolstad, Debra K. Czerwinski, Sébastien Wälchli, Michael R. Green, Gunhild Trøen, Knut Liestø, Klaus Beiske, Roch Houot, Jan Delabie, Ash A. Alizadeh, Jonathan M. Irish, Ronald Levy

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)759-770
Number of pages12
JournalBlood
Volume129
Issue number6
DOIs
StatePublished - Feb 9 2017

Fingerprint

B-Cell Antigen Receptors
Non-Hodgkin's Lymphoma
B-Lymphocytes
Cells
Mantle-Cell Lymphoma
Tumors
B-Cell Chronic Lymphocytic Leukemia
Protein-Tyrosine Kinases
Immunoglobulin M
Cell signaling
Phosphorylation
src-Family Kinases
Flow cytometry
Neoplasms
Extracellular Signal-Regulated MAP Kinases
Follicular Lymphoma
Type C Phospholipases
Lymphoma, Large B-Cell, Diffuse
B-Cell Lymphoma
Individuality

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Myklebust, J. H., Brody, J., Kohrt, H. E., Kolstad, A., Czerwinski, D. K., Wälchli, S., ... Levy, R. (2017). Distinct patterns of B-cell receptor signaling in non-Hodgkin lymphomas identified by single-cell profiling. Blood, 129(6), 759-770. https://doi.org/10.1182/blood-2016-05-718494

Distinct patterns of B-cell receptor signaling in non-Hodgkin lymphomas identified by single-cell profiling. / Myklebust, June H.; Brody, Joshua; Kohrt, Holbrook E.; Kolstad, Arne; Czerwinski, Debra K.; Wälchli, Sébastien; Green, Michael R.; Trøen, Gunhild; Liestø, Knut; Beiske, Klaus; Houot, Roch; Delabie, Jan; Alizadeh, Ash A.; Irish, Jonathan M.; Levy, Ronald.

In: Blood, Vol. 129, No. 6, 09.02.2017, p. 759-770.

Research output: Contribution to journalArticle

Myklebust, JH, Brody, J, Kohrt, HE, Kolstad, A, Czerwinski, DK, Wälchli, S, Green, MR, Trøen, G, Liestø, K, Beiske, K, Houot, R, Delabie, J, Alizadeh, AA, Irish, JM & Levy, R 2017, 'Distinct patterns of B-cell receptor signaling in non-Hodgkin lymphomas identified by single-cell profiling', Blood, vol. 129, no. 6, pp. 759-770. https://doi.org/10.1182/blood-2016-05-718494
Myklebust JH, Brody J, Kohrt HE, Kolstad A, Czerwinski DK, Wälchli S et al. Distinct patterns of B-cell receptor signaling in non-Hodgkin lymphomas identified by single-cell profiling. Blood. 2017 Feb 9;129(6):759-770. https://doi.org/10.1182/blood-2016-05-718494
Myklebust, June H. ; Brody, Joshua ; Kohrt, Holbrook E. ; Kolstad, Arne ; Czerwinski, Debra K. ; Wälchli, Sébastien ; Green, Michael R. ; Trøen, Gunhild ; Liestø, Knut ; Beiske, Klaus ; Houot, Roch ; Delabie, Jan ; Alizadeh, Ash A. ; Irish, Jonathan M. ; Levy, Ronald. / Distinct patterns of B-cell receptor signaling in non-Hodgkin lymphomas identified by single-cell profiling. In: Blood. 2017 ; Vol. 129, No. 6. pp. 759-770.
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