Synergy of NF-kB and Notch signaling in B cell lymphomatous transformation and B cell plasticity

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NF-kB and Notch signaling are activated in almost all common B cell lymphomas due to either activating somatic mutations or upregulation of pathway regulators. However, how these two pathways synergistically regulate B cell development and lymphomatous transformation are unclear. B cell plasticity has been recognized clinically decades ago. Patient with B cell lymphoma occasionally develop clonally-related myeloid tumors, suggesting that at least some myeloid tumors develop from malignant or premalignant B cells. Clinically, these patients typically present with advanced disease with a poor prognosis due to diagnostic difficulties and lack of standard treatment. The question is, how do B cells convert to myeloid lineage? Experimentally, forced expression of myeloid transcription factor, CEBPa, in mature B cells induces B-myeloid conversion. However, whether CEBPa initiates B-myeloid conversion in pathological conditions and whether other signaling pathways are also involved are largely unknown. Our preliminary data show that concurrent activation of both pathways in CD19+ B cells efficiently induces B cell lymphomatous transformation in sharp contrast to activation of either pathway alone. Intriguingly and unexpectedly, transplanted doubly-activated marginal zone precursor B cells, but not marginal zone B cells, converted to myeloid cells through dedifferentiation, and some transformed to myeloid leukemia with clonal immunoglobulin VDJ recombination. Our central hypothesis is that concurrent activation of NF-kB and Notch signaling accelerates B cell transformation and triggers B-myeloid conversion mainly through downregulation of Bach2 and upregulation of Ezh2. We will test this hypothesis with the following two independent specific aims: 1) To determine the mechanism whereby concurrent activation of NF-kB/Notch signaling induces B cell transformation, and 2) To determine the mechanism whereby concurrent activation of NF-kB/Notch signaling induces B-myeloid conversion and transformation. The expected results are highly relevant to understanding the synergistic role of NF-kB/Notch signaling in B cell plasticity and malignant transformation. Importantly, our results suggest that adding Notch, NF-kB and/or Ezh2 inhibitors to the current lymphoma therapeutic regimens could not only improve lymphoma treatment, but also prevent myeloid neoplasm conversion.