Coactivation of NF-κB and Notch signaling is sufficient to induce B-cell transformation and enables B-myeloid conversion
| Autor: | Thomas J. Waldschmidt, Meiling Jin, Hai-Hui Xue, Qianze Dong, Hasem Habelhah, Youzhong Yuan, Wei Wang, Ji Yuan, Chen Zhao, Nicholas Borcherding, Joseph D. Khoury, Iannis Aifantis, Qingchang Li, Brendan F. Boyce, Andrew L. Feldman, Markus Müschen, Lili Wang, Francesco Boccalatte, Shimin Hu, Benjamin W. Darbro, Endi Wang, Adam Bagg, Lin Fu, Yan Xiu, Aaron D. Bossler, Xiaobing Tang, Mariah R. Leidinger, Jose Luis Sardina, Siegfried Janz, John D. Colgan |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Myeloid Immunology Notch signaling pathway Biology Biochemistry Mice Downregulation and upregulation hemic and lymphatic diseases medicine Animals Humans Myeloid Cells Progenitor cell Transcription factor B cell B-Lymphocytes Lymphoid Neoplasia Receptors Notch Transdifferentiation NF-kappa B Myeloid leukemia Lymphoma B-Cell Marginal Zone Cell Biology Hematology Mice Inbred C57BL Cell Transformation Neoplastic medicine.anatomical_structure Cancer research Female Signal Transduction |
| Zdroj: | Blood |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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