KLF4‑mediated upregulation of the NKG2D ligand MICA in acute myeloid leukemia: a novel therapeutic target identified by enChIP
The immunoreceptor NKG2D, which is expressed on NK cells and T cell subsets is critically involved in tumor immune surveillance. This applies in particular to acute myeloid leukemia (AML), which evades immune detection by downregulation of NKG2D ligands (NKG2D-L), including MICA. The absence of NK...
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Main Authors: | , , , , , , |
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Format: | Article |
Language: | English |
Published: |
Philipps-Universität Marburg
2023
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Subjects: | |
Online Access: | PDF Full Text |
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Summary: | The immunoreceptor NKG2D, which is expressed on NK cells and T cell subsets is critically involved in tumor immune
surveillance. This applies in particular to acute myeloid leukemia (AML), which evades immune detection by downregulation
of NKG2D ligands (NKG2D-L), including MICA. The absence of NKG2D-L on AML cells is moreover associated
with leukemia stem cell characteristics. The NKG2D/NKG2D-L system thus qualifies as an interesting and promising
therapeutic target.
Here we aimed to identify transcription factors susceptible to pharmacological stimulation resulting in the expression
of the NKG2D-L MICA in AML cells to restore anti-tumor activity. Using a CRISPR-based engineered ChIP (enChIP) assay
for the MICA promoter region and readout by mass spectrometry-based proteomics, we identified the transcription
factor krüppel-like factor 4 (KLF4) as associated with the promoter. We demonstrated that the MICA promoter comprises
functional binding sites for KLF4 and genetic as well as pharmacological gain- and loss-of-function experiments
revealed inducible MICA expression to be mediated by KLF4.
Furthermore, induction in AML cells was achieved with the small compound APTO253, a KLF4 activator, which also
inhibits MYC expression and causes DNA damage. This induction in turn yielded increased expression and cell surface
presentation of MICA, thus rendering AML cells more susceptible to NK cell-mediated killing. These data unravel a
novel link between APTO253 and the innate anti-tumor immune response providing a rationale for targeting AML
cells via APTO253-dependent KFL4/MICA induction to allow elimination by endogenous or transplanted NK and T
cells in vivo. |
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Item Description: | Gefördert durch den Open-Access-Publikationsfonds der UB Marburg. |
Physical Description: | 14 Pages |
DOI: | 10.1186/s12964-023-01118-z |