Coactivation of NF-κB and Notch signaling is sufficient to induce B-cell transformation and enables B-myeloid conversion
Open Access
- 9 January 2020
- journal article
- research article
- Published by American Society of Hematology in Blood
- Vol. 135 (2), 108-120
- https://doi.org/10.1182/blood.2019001438
Abstract
NF-κB and Notch signaling can be simultaneously activated in a variety of B-cell lymphomas. Patients with B-cell lymphoma occasionally develop clonally related myeloid tumors with poor prognosis. Whether concurrent activation of both pathways is sufficient to induce B-cell transformation and whether the signaling initiates B-myeloid conversion in a pathological context are largely unknown. Here, we provide genetic evidence that concurrent activation of NF-κB and Notch signaling in committed B cells is sufficient to induce B-cell lymphomatous transformation and primes common progenitor cells to convert to myeloid lineage through dedifferentiation, not transdifferentiation. Intriguingly, the converted myeloid cells can further transform, albeit at low frequency, into myeloid leukemia. Mechanistically, coactivation of NF-κB and Notch signaling endows committed B cells with the ability to self renew. Downregulation of BACH2, a lymphoma and myeloid gene suppressor, but not upregulation of CEBPα and/or downregulation of B-cell transcription factors, is an early event in both B-cell transformation and myeloid conversion. Interestingly, a DNA hypomethylating drug not only effectively eliminated the converted myeloid leukemia cells, but also restored the expression of green fluorescent protein, which had been lost in converted myeloid leukemia cells. Collectively, our results suggest that targeting NF-κB and Notch signaling will not only improve lymphoma treatment, but also prevent the lymphoma-to-myeloid tumor conversion. Importantly, DNA hypomethylating drugs might efficiently treat these converted myeloid neoplasms.This publication has 84 references indexed in Scilit:
- The coding genome of splenic marginal zone lymphoma: activation of NOTCH2 and other pathways regulating marginal zone developmentThe Journal of Experimental Medicine, 2012
- Integrative Genomics Viewer (IGV): high-performance genomics data visualization and explorationBriefings in Bioinformatics, 2012
- Fast gapped-read alignment with Bowtie 2Nature Methods, 2012
- CCAAT/enhancer binding protein α (C/EBPα)-induced transdifferentiation of pre-B cells into macrophages involves no overt retrodifferentiationProceedings of the National Academy of Sciences of the United States of America, 2011
- BEDTools: a flexible suite of utilities for comparing genomic featuresBioinformatics, 2010
- Mutations of multiple genes cause deregulation of NF-κB in diffuse large B-cell lymphomaNature, 2009
- NIK overexpression amplifies, whereas ablation of its TRAF3-binding domain replaces BAFF:BAFF-R-mediated survival signals in B cellsProceedings of the National Academy of Sciences of the United States of America, 2008
- Direct Reprogramming of Terminally Differentiated Mature B Lymphocytes to PluripotencyCell, 2008
- Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined FactorsCell, 2006
- Nuclear factor-κB in cancer development and progressionNature, 2006