Coactivation of NF-κB and Notch signaling is sufficient to induce B-cell transformation and enables B-myeloid conversion.

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.

• Authors: Yan Xiu, Qianze Dong, Lin Fu, Aaron Bossler, Xiaobing Tang, Brendan Boyce, Nicholas Borcherding, Mariah Leidinger, José Luis Sardina, Hai-Hui Xue, Qingchang Li, Andrew Feldman, Iannis Aifantis, Francesco Boccalatte, Lili Wang, Meiling Jin, Joseph Khoury, Wei Wang, Shimin Hu, Youzhong Yuan, Endi Wang, Ji Yuan, Siegfried Janz, John Colgan, Hasem Habelhah, Thomas Waldschmidt, Markus Müschen, Adam Bagg, Benjamin Darbro, Chen Zhao
• Journal: Blood (Blood) Vol. 135 Issue 2 Pg. 108-120 (01 09 2020) ISSN: 1528-0020 [Electronic] United States
• PMID: 31697816 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• NF-kappa B
• Receptors, Notch

Topics

• Animals
• B-Lymphocytes (metabolism, pathology)
• Cell Transformation, Neoplastic (metabolism, pathology)
• Female
• Humans
• Lymphoma, B-Cell, Marginal Zone (genetics, metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Myeloid Cells (metabolism, pathology)
• NF-kappa B (genetics, metabolism)
• Receptors, Notch (genetics, metabolism)
• Signal Transduction