Bi-functional CpG-STAT3 decoy oligonucleotide triggers multilineage differentiation of acute myeloid leukemia in mice.

Autor:	Wang D; Department of Immuno-Oncology, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, CA, USA., Kaniowski D; Department of Immuno-Oncology, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, CA, USA., Jacek K; Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland., Su YL; Department of Immuno-Oncology, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, CA, USA., Yu C; Department of Immuno-Oncology, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, CA, USA., Hall J; Department of Immuno-Oncology, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, CA, USA., Li H; Integrative Genomics Core, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, USA., Feng M; Department of Immuno-Oncology, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, CA, USA., Hui S; Department of Radiation Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA., Kaminska B; Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland., DeFranciscis V; Institute of Genetic and Biomedical Research (IRGB), CNR, 20090 Milan Italy., Esposito CL; Institute for Experimental Endocrinology and Oncology 'Gaetano Salvatore' (IEOS), CNR, 80100 Naples, Italy., DiRuscio A; Harvard Medical School Initiative for RNA Medicine, Harvard Medical School, Boston, MA 02115, USA., Zhang B; Department of Hematologic Malignancies Translational Science, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, CA, USA.; Gehr Family Center for Leukemia Research, City of Hope Comprehensive Cancer Center, Duarte, CA, USA., Marcucci G; Department of Hematologic Malignancies Translational Science, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, CA, USA.; Gehr Family Center for Leukemia Research, City of Hope Comprehensive Cancer Center, Duarte, CA, USA., Kuo YH; Department of Hematologic Malignancies Translational Science, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, CA, USA.; Gehr Family Center for Leukemia Research, City of Hope Comprehensive Cancer Center, Duarte, CA, USA., Kortylewski M; Department of Immuno-Oncology, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Nucleic acids [Mol Ther Nucleic Acids] 2024 Jul 16; Vol. 35 (3), pp. 102268. Date of Electronic Publication: 2024 Jul 16 (Print Publication: 2024).
DOI:	10.1016/j.omtn.2024.102268
Abstrakt:	Acute myeloid leukemia (AML) cells resist differentiation stimuli despite high expression of innate immune receptors, such as Toll-like receptor 9 (TLR9). We previously demonstrated that targeting Signal Transducer and Activator of Transcription 3 (STAT3) using TLR9-targeted decoy oligodeoxynucleotide (CpG-STAT3d) increases immunogenicity of human and mouse AML cells. Here, we elucidated molecular mechanisms of inv(16) AML reprogramming driven by STAT3-inhibition/TLR9-activation in vivo . At the transcriptional levels, AML cells isolated from mice after intravenous administration of CpG-STAT3d or leukemia-targeted Stat3 silencing and TLR9 co-stimulation, displayed similar upregulation of myeloid cell differentiation ( Irf8, Cebpa, Itgam ) and antigen-presentation ( Ciita, Il12a, B2m )-related genes with concomitant reduction of leukemia-promoting Runx1 . Single-cell transcriptomics revealed that CpG-STAT3d induced multilineage differentiation of AML cells into monocytes/macrophages, erythroblastic and B cell subsets. As shown by an inducible Irf8 silencing in vivo , IRF8 upregulation was critical for monocyte-macrophage differentiation of leukemic cells. TLR9-driven AML cell reprogramming was likely enabled by downregulation of STAT3-controlled methylation regulators, such as DNMT1 and DNMT3. In fact, the combination of DNA methyl transferase (DNMT) inhibition using azacitidine with CpG oligonucleotides alone mimicked CpG-STAT3d effects, resulting in AML cell differentiation, T cell activation, and systemic leukemia regression. These findings highlight immunotherapeutic potential of bi-functional oligonucleotides to unleash TLR9-driven differentiation of leukemic cells by concurrent STAT3 and/or DNMT inhibition. Competing Interests: M.K. is an inventor on the patents that cover the design of CpG-STAT3d ODNs. M.K. serves on the Scientific Advisory Board of Scopus Biopharma and its subsidiary Duet Biotherapeutics with stock options and sponsored research. (© 2024 The Author(s).)
Databáze:	MEDLINE
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