TIFAB accelerates MLL-AF9−Induced acute myeloid leukemia through upregulation of HOXA9
Jinming Zhao,
Yan Xiu,
Lin Fu,
Qianze Dong,
Nicholas Borcherding,
Yang Wang,
Qingchang Li,
Nilushi S. De Silva,
Ulf Klein,
Brendan F. Boyce,
Chen Zhao
Affiliations
Jinming Zhao
Department of Pathology, Case Western Reserve University, Wolstein Research Building, Room 6503 2103 Cornell Road, Cleveland, OH 44106, USA; Department of Pathology, China Medical University, 77 Puhe Road, Shenbei Xinqu, Shenyang, Liaoning Province, 110122, China
Yan Xiu
Department of Pathology, Case Western Reserve University, Wolstein Research Building, Room 6503 2103 Cornell Road, Cleveland, OH 44106, USA; Department of Pathology, Louis Stokes Veterans Affairs Medical Center, Cleveland, OH 44106, USA
Lin Fu
Department of Pathology, China Medical University, 77 Puhe Road, Shenbei Xinqu, Shenyang, Liaoning Province, 110122, China
Qianze Dong
Department of Pathology, Case Western Reserve University, Wolstein Research Building, Room 6503 2103 Cornell Road, Cleveland, OH 44106, USA; Department of Pathology, Louis Stokes Veterans Affairs Medical Center, Cleveland, OH 44106, USA
Nicholas Borcherding
Department of Pathology and Immunology, Barnes-Jewish Hospital, Washington University in St Louis, MO 63110, USA
Yang Wang
Department of Pathology, Case Western Reserve University, Wolstein Research Building, Room 6503 2103 Cornell Road, Cleveland, OH 44106, USA
Qingchang Li
Department of Pathology, China Medical University, 77 Puhe Road, Shenbei Xinqu, Shenyang, Liaoning Province, 110122, China
Nilushi S. De Silva
Institut Curie, PSL Research University, INSERM U932, Paris, France
Ulf Klein
Division of Haematology & Immunology, Leeds Institute of Medical Research at St. James, Leeds LS9 7TF, UK
Brendan F. Boyce
Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
Chen Zhao
Department of Pathology, Louis Stokes Veterans Affairs Medical Center, Cleveland, OH 44106, USA; Department of Pathology, University Hospitals Case Medical Center, Cleveland, OH 44106, USA; Department of Pathology, Case Western Reserve University, Wolstein Research Building, Room 6523 2103 Cornell Road, Cleveland, OH 44106, USA; Corresponding author
Summary: 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.
