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Coactivation of NF-κB and Notch signaling is sufficient to induce B-cell transformation and enables B-myeloid conversion. Blood 2020 01 09;135(2):108-120

Date

11/08/2019

Pubmed ID

31697816

Pubmed Central ID

PMC6952829

DOI

10.1182/blood.2019001438

Scopus ID

2-s2.0-85077760977   5 Citations

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.

Author List

Xiu Y, Dong Q, Fu L, Bossler A, Tang X, Boyce B, Borcherding N, Leidinger M, Sardina JL, Xue HH, Li Q, Feldman A, Aifantis I, Boccalatte F, Wang L, Jin M, Khoury J, Wang W, Hu S, Yuan Y, Wang E, Yuan J, Janz S, Colgan J, Habelhah H, Waldschmidt T, Müschen M, Bagg A, Darbro B, Zhao C

Author

Siegfried Janz MD Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

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