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TIFAB accelerates MLL-AF9-Induced acute myeloid leukemia through upregulation of HOXA9.

ABSTRACT: 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.

SUBMITTER: Zhao J

PROVIDER: S-EPMC8633042 | biostudies-literature |

REPOSITORIES: biostudies-literature

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TIFAB Accelerates MLL-AF9-Induced Acute Myeloid Leukemia Through Upregulation of HOXA9

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TIFAB Accelerates MLL-AF9-Induced Acute Myeloid Leukemia Through Upregulation of HOXA9

Project description:TIFAB Accelerates MLL-AF9-Induced Acute Myeloid Leukemia Through Upregulation of HOXA9

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Project description:Acute myeloid leukemia (AML) is defined by an accumulation of immature myeloid blasts in the bone marrow. To identify key dependencies of AML stem cells in vivo, here we use a CRISPR-Cas9 screen targeting cell surface genes in a syngeneic MLL-AF9 AML mouse model and show that CXCR4 is a top cell surface regulator of AML cell growth and survival. Deletion of Cxcr4 in AML cells eradicates leukemia cells in vivo without impairing their homing to the bone marrow. In contrast, the CXCR4 ligand CXCL12 is dispensable for leukemia development in recipient mice. Moreover, expression of mutated Cxcr4 variants reveals that CXCR4 signaling is essential for leukemia cells. Notably, loss of CXCR4 signaling in leukemia cells leads to oxidative stress and differentiation in vivo. Taken together, our results identify CXCR4 signaling as essential for AML stem cells by protecting them from differentiation independent of CXCL12 stimulation.

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