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Coactivation of NF-κB and Notch signaling is sufficient to induce B-cell transformation and enables B-myeloid conversion.
Xiu, Yan; Dong, Qianze; Fu, Lin; Bossler, Aaron; Tang, Xiaobing; Boyce, Brendan; Borcherding, Nicholas; Leidinger, Mariah; Sardina, José Luis; Xue, Hai-Hui; Li, Qingchang; Feldman, Andrew; Aifantis, Iannis; Boccalatte, Francesco; Wang, Lili; Jin, Meiling; Khoury, Joseph; Wang, Wei; Hu, Shimin; Yuan, Youzhong; Wang, Endi; Yuan, Ji; Janz, Siegfried; Colgan, John; Habelhah, Hasem; Waldschmidt, Thomas; Müschen, Markus; Bagg, Adam; Darbro, Benjamin; Zhao, Chen.
Afiliación
  • Xiu Y; Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA.
  • Dong Q; Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA.
  • Fu L; Department of Pathology, China Medical University, Shenyang, China.
  • Bossler A; Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA.
  • Tang X; Department of Pathology, China Medical University, Shenyang, China.
  • Boyce B; Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA.
  • Borcherding N; Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA.
  • Leidinger M; Department of Pathology, China Medical University, Shenyang, China.
  • Sardina JL; Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY.
  • Xue HH; Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA.
  • Li Q; Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA.
  • Feldman A; Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain.
  • Aifantis I; Josep Carreras Leukaemia Research Institute, Campus ICO-Germans Trias i Pujol, Barcelona, Spain.
  • Boccalatte F; Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA.
  • Wang L; Department of Pathology, China Medical University, Shenyang, China.
  • Jin M; Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN.
  • Khoury J; Department of Pathology, NYU School of Medicine, New York, NY.
  • Wang W; Department of Pathology, NYU School of Medicine, New York, NY.
  • Hu S; Department of Systems Biology, Beckman Research Institute, City of Hope, Monrovia, CA.
  • Yuan Y; Department of Systems Biology, Beckman Research Institute, City of Hope, Monrovia, CA.
  • Wang E; Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX.
  • Yuan J; Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX.
  • Janz S; Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX.
  • Colgan J; Department of Pathology, University of Arkansas for Medical Science, Little Rock, AR.
  • Habelhah H; Department of Pathology, Duke University Medical Center, Durham, NC.
  • Waldschmidt T; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE.
  • Müschen M; Department of Medicine, Medical College of Wisconsin, Milwaukee, WI.
  • Bagg A; Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA.
  • Darbro B; Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA.
  • Zhao C; Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA.
Blood ; 135(2): 108-120, 2020 01 09.
Article en En | MEDLINE | ID: mdl-31697816
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Linfocitos B / Transformación Celular Neoplásica / FN-kappa B / Linfoma de Células B de la Zona Marginal / Células Mieloides / Receptores Notch Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: Blood Año: 2020 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
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XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Linfocitos B / Transformación Celular Neoplásica / FN-kappa B / Linfoma de Células B de la Zona Marginal / Células Mieloides / Receptores Notch Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: Blood Año: 2020 Tipo del documento: Article Pais de publicación: Estados Unidos