TIFAB accelerates MLL-AF9-Induced acute myeloid leukemia through upregulation of HOXA9.
TIFAB accelerates MLL-AF9-Induced acute myeloid leukemia through upregulation of HOXA9.
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DOI：
10.1016/j.isci.2021.103425
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发表时间：
2021-12-17
期刊：
影响因子：
5.8
通讯作者：
Zhao C
中科院分区：
文献类型：
--
作者：
Zhao J;Xiu Y;Fu L;Dong Q;Borcherding N;Wang Y;Li Q;De Silva NS;Klein U;Boyce BF;Zhao C
我们之前已经证明NIK-诱导的NF-κB非经典信号的激活的稳定性抑制MLL-AF 9-诱导的AML。在目前的研究中，我们证明了NF-κB非经典RelB的缺失阻止了MLL-AF 9 AML中NIK稳定化的抑制作用。从机制上讲，RelB抑制其直接靶点TIFAB，TIFAB在人AML中上调，并与AML患者的生存率呈负相关。TIFAB的强制表达通过下调RelB和上调HOXA 9逆转NIK诱导的受损AML发展。与HOXA 9的上调一致，基因集富集分析显示，TIFAB的强制表达阻断骨髓细胞发育，上调白血病干细胞特征并诱导与HOXA 9-MEIS 1和HOXA 9-NUP 98相似的基因表达模式，并上调氧化磷酸化。因此，HOXA 9的强制表达也通过RelB的下调和RelA的上调在很大程度上释放了NIK稳定的抑制作用。我们的数据表明，NIK/RelB主要通过下调TIFAB/HOXA 9来抑制MLL-AF 9-诱导的AML。RelB对稳定NIK诱导的AML抑制至关重要TIFAB是MLL-AF 9诱导的AML中的直接RelB靶点TIFAB通过上调HOXA 9加速MLL-AF 9诱导的AML生物科学;分子生物学;癌症
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. RelB is essential for stabilization of NIK−induced AML suppression TIFAB is a direct RelB target in MLL-AF9−induced AML TIFAB accelerates MLL-AF9−induced AML via upregulation of HOXA9 Biological sciences; Molecular biology; Cancer
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影响因子：
23.9
作者：
Lagadinou, Eleni D.;Sach, Alexander;Callahan, Kevin;Rossi, Randall M.;Neering, Sarah J.;Minhajuddin, Mohammad;Ashton, John M.;Pei, Shanshan;Grose, Valerie;O'Dwyer, Kristen M.;Liesveld, Jane L.;Brookes, Paul S.;Becker, Michael W.;Jordan, Craig T.
通讯作者：
Jordan, Craig T.
影响因子：
8
作者：
Collins CT;Hess JL
通讯作者：
Hess JL
影响因子：
2.1
作者：
Jordan, Craig T.
通讯作者：
Jordan, Craig T.
影响因子：
16
作者：
Milne, TA;Briggs, SD;Hess, JL
通讯作者：
Hess, JL
DOI：
10.1073/pnas.1602728113
发表时间：
2016-08-09
影响因子：
11.1
作者：
De Silva, Nilushi S.;Anderson, Michael M.;Klein, Ulf
通讯作者：
Klein, Ulf