TY - JOUR
T1 - Coactivation of NF-kB and Notch signaling is sufficient to induce B-cell transformation and enables B-myeloid conversion
AU - Xiu, Yan
AU - Dong, Qianze
AU - Fu, Lin
AU - Bossler, Aaron
AU - Tang, Xiaobing
AU - Boyce, Brendan
AU - Borcherding, Nicholas
AU - Leidinger, Mariah
AU - Sardina, José Luis
AU - Xue, Hai hui
AU - Li, Qingchang
AU - Feldman, Andrew
AU - Aifantis, Iannis
AU - Boccalatte, Francesco
AU - Wang, Lili
AU - Jin, Meiling
AU - Khoury, Joseph
AU - Wang, Wei
AU - Hu, Shimin
AU - Yuan, Youzhong
AU - Wang, Endi
AU - Yuan, Ji
AU - Janz, Siegfried
AU - Colgan, John
AU - Habelhah, Hasem
AU - Waldschmidt, Thomas
AU - Müschen, Markus
AU - Bagg, Adam
AU - Darbro, Benjamin
AU - Zhao, Chen
N1 - Publisher Copyright:
© 2020 American Society of Hematology. All rights reserved.
PY - 2020/1/9
Y1 - 2020/1/9
N2 - NF-kB 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-kB 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-kB 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 CEBPa 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-kB 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.
AB - NF-kB 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-kB 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-kB 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 CEBPa 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-kB 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.
UR - http://www.scopus.com/inward/record.url?scp=85077760977&partnerID=8YFLogxK
U2 - 10.1182/blood.2019001438
DO - 10.1182/blood.2019001438
M3 - Article
C2 - 31697816
AN - SCOPUS:85077760977
SN - 0006-4971
VL - 135
SP - 108
EP - 120
JO - Blood
JF - Blood
IS - 2
ER -