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STAT3 inhibition permits epigenetic reprogramming and TLR9/IRF8-driven differentiation of inv(16) acute myeloid leukemia.

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE233099 | GEO | 2024/07/23

REPOSITORIES: GEO

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STAT3 inhibition permits epigenetic reprogramming and TLR9/IRF8-driven differentiation of inv(16) acute myeloid leukemia [RNASEQ_AML_CPGDOX]

Project description:Cultured acute myeloid leukemia (AML) blasts can differentiate into antigen-presenting cells but achieving leukemic cell immunogenicity proved challenging in clinical setting. Despite expressing multiple immunostimulatory receptors, such as Toll-like Receptor 9 (TLR9), AML cells resist immunostimulation. We previously demonstrated that eliminating Signal Transducer and Activator of Transcription 1 and 3 (STAT1/3) signaling in AML cells using decoy DNA strategy (CpG-STAT3dODN) synergized with TLR9 stimulation and resulted in T cell-mediated leukemia regression. Here, we interrogated the molecular underpinnings of CpG-STAT3dODN-driven differentiation and immunogenicity of mouse Cbfb/MYH11/Mpl AML. The transcriptional profiling of AML cells isolated from mice after inducible Stat3 silencing plus TLR9 stimulation or CpG-STAT3dODN treatment, revealed comparable upregulation of genes related to myeloid cell differentiation (Irf8, Cebpa) and immune stimulation (Gadd45a, Ciita, Il12a, Ifng) but decreased expression of leukemia-promoting Runx1 and Run1t1. The conditional Irf8 silencing in AML cells almost completely abrogated TLR9-driven leukemia cell differentiation. The AML cell reprogramming by CpG-STAT3dODN was likely regulated epigenetically as revealed by reduced global promoter hypomethylation of crucial myeloid cell differentiation and immune activation genes. These changes were associated with reduced expression of known STAT3 targets, DNMT1 and DNMT3a/b. Finally, we provide initial evidence of anti-leukemic effects of CpG-STAT3 inhibitor against human AML model in humanized mice. Our studies suggest that, beyond oncogenic functions, STAT3 in AML cells may be a primary checkpoint in control of immune-stimulatory and differentiation driving effects. These findings support further development of CpG-STAT3 inhibitors as a new bi-functional agents for AML immunotherapy.

2024-07-23 | GSE233095 | GEO

STAT3 inhibition permits epigenetic reprogramming and TLR9/IRF8-driven differentiation of inv(16) acute myeloid leukemia [RRBS]

2024-07-23 | GSE233097 | GEO

STAT3 inhibition permits epigenetic reprogramming and TLR9/IRF8-driven differentiation of inv(16) acute myeloid leukemia [RNASEQ_AML_DECSCR]

2024-07-23 | GSE233096 | GEO

STAT3 inhibition permits epigenetic reprogramming and TLR9/IRF8-driven differentiation of inv(16) acute myeloid leukemia [scRNA-seq]

2024-07-23 | GSE233098 | GEO

STAT3 inhibition permits epigenetic reprogramming and TLR9/IRF8-driven differentiation of inv(16) acute myeloid leukemia.

Project description:STAT3 inhibition permits epigenetic reprogramming and TLR9/IRF8-driven differentiation of inv(16) acute myeloid leukemia.

| PRJNA974904 | ENA

STAT3 inhibition permits epigenetic reprogramming and TLR9/IRF8-driven differentiation of inv(16) acute myeloid leukemia [RRBS]

Project description:STAT3 inhibition permits epigenetic reprogramming and TLR9/IRF8-driven differentiation of inv(16) acute myeloid leukemia [RRBS]

| PRJNA974913 | ENA

STAT3 inhibition permits epigenetic reprogramming and TLR9/IRF8-driven differentiation of inv(16) acute myeloid leukemia [RNASEQ_AML_CPGDOX]

Project description:STAT3 inhibition permits epigenetic reprogramming and TLR9/IRF8-driven differentiation of inv(16) acute myeloid leukemia [RNASEQ_AML_CPGDOX]

| PRJNA974911 | ENA

STAT3 inhibition permits epigenetic reprogramming and TLR9/IRF8-driven differentiation of inv(16) acute myeloid leukemia [RNASEQ_AML_DECSCR]

Project description:STAT3 inhibition permits epigenetic reprogramming and TLR9/IRF8-driven differentiation of inv(16) acute myeloid leukemia [RNASEQ_AML_DECSCR]

| PRJNA974912 | ENA

STAT3 inhibition permits epigenetic reprogramming and TLR9/IRF8-driven differentiation of inv(16) acute myeloid leukemia [scRNA-seq]

Project description:STAT3 inhibition permits epigenetic reprogramming and TLR9/IRF8-driven differentiation of inv(16) acute myeloid leukemia [scRNA-seq]

| PRJNA974914 | ENA

HDAC8 Inhibition Specifically Targets Inv(16) Acute Myeloid Leukemic Stem Cells by Restoring p53 Acetylation.

Project description:Acute myeloid leukemia (AML) is driven and sustained by leukemia stem cells (LSCs) with unlimited self-renewal capacity and resistance to chemotherapy. Mutation in the TP53 tumor suppressor is relatively rare in de novo AML; however, p53 can be regulated through post-translational mechanisms. Here, we show that p53 activity is inhibited in inv(16)(+) AML LSCs via interactions with the CBF?-SMMHC (CM) fusion protein and histone deacetylase 8 (HDAC8). HDAC8 aberrantly deacetylates p53 and promotes LSC transformation and maintenance. HDAC8 deficiency or inhibition using HDAC8-selective inhibitors (HDAC8i) effectively restores p53 acetylation and activity. Importantly, HDAC8 inhibition induces apoptosis in inv(16)(+) AML CD34(+) cells, while sparing the normal hematopoietic stem cells. Furthermore, in vivo HDAC8i administration profoundly diminishes AML propagation and abrogates leukemia-initiating capacity of both murine and patient-derived LSCs. This study elucidates an HDAC8-mediated p53-inactivating mechanism promoting LSC activity and highlights HDAC8 inhibition as a promising approach to selectively target inv(16)(+) LSCs.

| S-EPMC4636961 | biostudies-literature

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