General Information
- Project ID
- OEP004811
- Project Name
- Loss of Setd2 induces systemic inflammation via embryo-derived Kupffer-like cell differentiation to drive malignant transformation
- Description
- SETD2, a specific histone H3 lysine 36 tri-methyltransferase, is recurrently mutated in hematopoietic malignancies. Setd2 deficiency impairs the self-renewal and competitive potential of hematopoietic stem/progenitor cells (HSPCs), while it promotes a myelodysplastic syndrome-like (MDS) transformation. Nevertheless, the precise oncogenic advantages conferred upon HSPCs by Setd2 loss remain inadequately elucidated. Here, we observed that diseased HSPCs, with completely loss of self-renewal capabilities, can differentiate into embryo-derived Kupffer-like cells, characterized by heightened competitive ability, proliferation, and exacerbated inflammatory effects. The Kupffer-like cells sustain persistent systemic inflammation, thereby forcing the malignant transformation process. Notably, macrophage depletion effectively ameliorates the inflammatory state and alleviates MDS-like symptoms. Mechanistically, loss of Setd2 induces substantial alterations in DNA methylation patterns and chromatin accessibility, which instigate the activation of Irf8 synergistically and/or independently. Consequently, our study posits the notion that the long-lived inflammatory cells differentiated from HSPCs compensate the impaired self-renewal and induce malignant transformation independently.
- Related Links
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Project information
Author Information
- Create Date
- 2023-12-07
- Last Modified
- 2024-02-27
- Submission
- Yuanliang Zhang
- Shanghai Institute of Hematology