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Oridonin inhibits DNMT3A R882 mutation-driven clonal hematopoiesis and leukemia by inducing apoptosis and necroptosis.

ABSTRACT: DNA (cytosine-5)-methyltransferase 3A (DNMT3A) mutations occur in ~20% of de novo acute myeloid leukemia (AML) patients, and >50% of these mutations in AML samples are heterozygous missense alterations within the methyltransferase domain at residue R882. DNMT3A R882 mutations in AML patients promote resistance to anthracycline chemotherapy and drive relapse. In this study, we performed high-throughput screening and identified that oridonin, an ent-kaurene diterpenoid extracted from the Chinese herb Rabdosia rubescens, inhibits DNMT3A R882 mutant leukemic cells at a low-micromolar concentration (IC₅₀ = 2.1 µM) by activating both RIPK1-Caspase-8-Caspase-3-mediated apoptosis and RIPK1-RIPK3-MLKL-mediated necroptosis. The inhibitory effect of oridonin against DNMT3A R882 mutant leukemia cells can also be observed in vivo. Furthermore, oridonin inhibits clonal hematopoiesis of hematopoietic stem cells (HSCs) with Dnmt3a R878H mutation comparing to normal HSCs by inducing apoptosis and necroptosis. Overall, oridonin is a potential and promising drug candidate or lead compound targeting DNMT3A R882 mutation-driven clonal hematopoiesis and leukemia.

SUBMITTER: Liao M

PROVIDER: S-EPMC8523644 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Aging-elevated inflammation promotes DNMT3A R878H-driven clonal hematopoiesis.

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2023-02-19 | E-MTAB-12614 | biostudies-arrayexpress

Inflammatory signals from fatty bone marrow support DNMT3a-driven clonal hematopoiesis (Dnmt3A KI heterozygote subset)

2023-02-19 | E-MTAB-12613 | biostudies-arrayexpress

Recurrent DNMT3A R882 mutations in Chinese patients with acute myeloid leukemia and myelodysplastic syndrome.

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Clonal hematopoiesis with DNMT3A mutation is associated with lower white matter hyperintensity volume.

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