Journal article
Coactivation of NF-κB and Notch signaling is sufficient to induce B-cell transformation and enables B-myeloid conversion
Blood, Vol.135(2), pp.108-120
01/09/2020
DOI: 10.1182/blood.2019001438
PMID: 31697816
Abstract
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.
Details
- Title: Subtitle
- Coactivation of NF-κB and Notch signaling is sufficient to induce B-cell transformation and enables B-myeloid conversion
- Creators
- Yan Xiu - University of IowaQianze Dong - University of IowaLin Fu - University of IowaAaron Bossler - University of IowaNicholas Borcherding - University of IowaXiaobing Tang - University of IowaMariah Leidinger - University of IowaBrendan Boyce - University of RochesterHai-hui Xue - University of IowaSiegfried Janz - Medical College of WisconsinJohn Colgan - University of IowaJosé Luis Sardina - Centre for Genomic RegulationHasem Habelhah - University of IowaThomas Waldschmidt - University of IowaQingchang Li - China Medical University (PRC)Benjamin Darbro - University of IowaAndrew Feldman - Mayo ClinicChen Zhao - Iowa City VA Medical CenterIannis Aifantis - York UniversityFrancesco Boccalatte - York UniversityLili WangMeiling JinJoseph Khoury - The University of Texas MD Anderson Cancer CenterWei Wang - The University of Texas MD Anderson Cancer CenterShimin Hu - The University of Texas MD Anderson Cancer CenterYouzhong Yuan - University of ArkansasEndi Wang - Duke UniversityJi Yuan - University of Nebraska Medical CenterMarkus MüschenAdam Bagg - University of Pennsylvania
- Resource Type
- Journal article
- Publication Details
- Blood, Vol.135(2), pp.108-120
- DOI
- 10.1182/blood.2019001438
- PMID
- 31697816
- ISSN
- 0006-4971
- eISSN
- 1528-0020
- Language
- English
- Date published
- 01/09/2020
- Academic Unit
- Dermatology; Microbiology and Immunology; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Pathology; Medical Genetics and Genomics; Immunology; Internal Medicine
- Record Identifier
- 9984184000002771
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