TY - JOUR
T1 - TIFAB accelerates MLL-AF9−Induced acute myeloid leukemia through upregulation of HOXA9
AU - Zhao, Jinming
AU - Xiu, Yan
AU - Fu, Lin
AU - Dong, Qianze
AU - Borcherding, Nicholas
AU - Wang, Yang
AU - Li, Qingchang
AU - De Silva, Nilushi S.
AU - Klein, Ulf
AU - Boyce, Brendan F.
AU - Zhao, Chen
N1 - Publisher Copyright:
© 2021 The Author(s)
PY - 2021/12/17
Y1 - 2021/12/17
N2 - We previously showed stabilization of NIK−induced activation of NF-κB non-canonical signaling suppresses MLL-AF9−induced AML. In the current study, we demonstrate that deletion of NF-κB non-canonical RelB prevents the inhibitory effect of NIK stabilization in MLL-AF9 AML. Mechanistically, RelB suppresses its direct target, TIFAB, which is upregulated in human AML and correlates negatively with the survival of AML patients. Forced expression of TIFAB reverses NIK−induced impaired AML development through downregulation of RelB and upregulation of HOXA9. Consistent with upregulation of HOXA9, gene set enrichment analysis shows that forced expression of TIFAB blocks myeloid cell development, upregulates leukemia stem cell signature and induces similar gene expression patterns to those of HOXA9-MEIS1 and HOXA9-NUP98, and upregulates oxidative phosphorylation. Accordingly, forced expression of HOXA9 also largely releases the inhibitory impact of NIK stabilization via downregulation of RelB and upregulation of RelA. Our data suggest that NIK/RelB suppresses MLL-AF9−induced AML mainly through downregulation of TIFAB/HOXA9.
AB - We previously showed stabilization of NIK−induced activation of NF-κB non-canonical signaling suppresses MLL-AF9−induced AML. In the current study, we demonstrate that deletion of NF-κB non-canonical RelB prevents the inhibitory effect of NIK stabilization in MLL-AF9 AML. Mechanistically, RelB suppresses its direct target, TIFAB, which is upregulated in human AML and correlates negatively with the survival of AML patients. Forced expression of TIFAB reverses NIK−induced impaired AML development through downregulation of RelB and upregulation of HOXA9. Consistent with upregulation of HOXA9, gene set enrichment analysis shows that forced expression of TIFAB blocks myeloid cell development, upregulates leukemia stem cell signature and induces similar gene expression patterns to those of HOXA9-MEIS1 and HOXA9-NUP98, and upregulates oxidative phosphorylation. Accordingly, forced expression of HOXA9 also largely releases the inhibitory impact of NIK stabilization via downregulation of RelB and upregulation of RelA. Our data suggest that NIK/RelB suppresses MLL-AF9−induced AML mainly through downregulation of TIFAB/HOXA9.
KW - Biological sciences
KW - Cancer
KW - Molecular biology
UR - http://www.scopus.com/inward/record.url?scp=85120993601&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2021.103425
DO - 10.1016/j.isci.2021.103425
M3 - Article
AN - SCOPUS:85120993601
SN - 2589-0042
VL - 24
JO - iScience
JF - iScience
IS - 12
M1 - 103425
ER -