Epigenetic Control over IFN Type-I Response antagonizes self-renewal in acute myeloid leukemia 

ABSTRACT: Large biological heterogeneity hallmarks acute myeloid leukemia (AML) and substantially hampers development of novel comprehensive therapies. While all-trans retinoic acid (ATRA) revolutionized therapy of acute promyelocytic leukemia, its impact on other AML subtypes remained largely disappointing. Here we show for the first time that ATRA mediated phosphorylation of the histone demethylase PHF8 induces apoptosis of AML cells of different subtypes via regulation of viral mimicry and subsequent initiation of interferon (IFN) type-I response. Phospho-PHF8 conferred H3K9me2 demethylation at promoter sites of key initiators of cell-intrinsic immune response. Multiomics based analyses revealed activation of cytosolic RNA sensors as key step towards NF-κB driven IFN type-I mediated apoptosis. Epigenetic changes directed by PHF8 also induced a specific proteosome pathway controlling NF-κB activity after its initial activation. Hence, PHF8 orchestrates viral mimicry, triggering IFN type-I response-differentiation-apoptotic network in a broad spectrum of AML when activated by ATRA. Forced phosphorylation of PHF8 via combination treatment with ATRA and simultaneous pharmacological inhibition of PHF8 dephosphorylation significantly impaired growth of human AML. Our findings finally open the gate for successful application of ATRA-based combination therapies in AML.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Cell, Cell Culture

DISEASE(S): Acute Leukemia

SUBMITTER: Ashokkumar Jayavelu  

LAB HEAD: Dr.Ashok Kumar Jayavelu

PROVIDER: PXD035635 | Pride | 2024-06-22

REPOSITORIES: Pride