Roland, L. | Search bioRxiv

bioRxiv2019

B-cell enforced expression of the mouse ortholog of MYD88L265P is responsible for Waldenstrom-like B-cell lymphoma.

Here, we created a conditional transgenic mouse model with insertion of a sequence coding for both MYD88L252P and the Yellow Fluorescent Protein (YFP) into the rosa26-locus. B-cell specific induction of the transgene constantly led to spleen enlargement with expansion of YFP positive B-cells in 8-12 month-old mice, with a moderate B-cell proliferation increase. Being clonal or oligoclonal, these B-cells exhibited a marked morphological and immunophenotypic lymphoplasmocytic aspect with a plasma cell transcriptomic signature and a serum immunoglobulin M peak. Therefore, continuous activation of MYD88 in mice can lead on its own to a lymphoma close to Waldenstrom Macroglobulinemia.\n\nKey pointB-cell specific enforced expression of MYD88L252P leads to a clonal indolent lymphoplasmocytic B-cell lymphoma with a serum IgM peak.

cancer biology↗

bioRxiv2018

Pre-Clinical Blocking of PD-L1 molecule, which expression is down regulated by NF-κB, JAK1/JAK2 and BTK inhibitors, induces regression of activated B-cell lymphoma.

Escape from immune control must be important in the natural course of B-cell lymphomas, especially for those with activation of NF-{kappa}B. The pre-clinical L.CD40 transgenic mouse model is characterized by B-cell specific CD40 signaling responsible for NF-{kappa}B continuous activation with a spleen monoclonal B-cell tumor after one year in 60% of cases. L.CD40 tumors B-cells expressed high levels of PD-L1. This expression was dependent on activation of either NF-{kappa}B, JAK1/JAK2 or BTK pathways since ex vivo treatment with the inhibitory molecules PHA-408, ruxolitinib and ibrutinib led to decrease of its expression. Treatment of L.CD40 lymphomatous mice with an anti-PD-L1 monoclonal antibody induced tumor regression with decreased spleen content, activation and proliferation rate of B-cells as well as a marked increase in T cell activation, as assessed by CD62L and CD44 expression. These results highlight the interest of therapies targeting the PD-1/PD-L1 axis in activated lymphomas with PD-L1 expression, with possible synergies with tyrosine kinase inhibitors.

cancer biology↗