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ACUTE MYELOID LEUKEMIA

CDK19 regulates the proliferation of hematopoietic stem cells and acute myeloid leukemia cells by suppressing p53-mediated transcription of p21

Abstract

The cell cycle progression of hematopoietic stem cells (HSCs) and acute myeloid leukemia (AML) cells is precisely controlled by multiple regulatory factors. However, the underlying mechanisms are not fully understood. Here, we find that cyclin-dependent kinase 19 (CDK19), not its paralogue CDK8, is relatively enriched in mouse HSCs, and its expression is more significantly increased than CDK8 after proliferative stresses. Furthermore, SenexinB (a CDK8/19 inhibitor) treatment impairs the proliferation and self-renewal ability of HSCs. Moreover, overexpression of CDK19 promotes HSC function better than CDK8 overexpression. Using CDK19 knockout mice, we observe that CDK19−/− HSCs exhibit similar phenotypes to those of cells treated with SenexinB. Interestingly, the p53 signaling pathway is significantly activated in HSCs lacking CDK19 expression. Further investigations show that CDK19 can interact with p53 to inhibit p53-mediated transcription of p21 in HSCs and treatment with a specific p53 inhibitor (PFTβ) partially rescues the defects of CDK19-null HSCs. Importantly, SenexinB treatment markedly inhibits the proliferation of AML cells. Collectively, our findings indicate that CDK19 is involved in regulating HSC and AML cell proliferation via the p53-p21 pathway, revealing a new mechanism underlying cell cycle regulation in normal and malignant hematopoietic cells.

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Fig. 1: CDK19 expression is upregulated in HSCs after exposure to stresses that induce proliferation.
Fig. 2: SenexinB (CDK8/19 inhibitor) treatment attenuates the proliferation and function of HSCs.
Fig. 3: Overexpression of CDK19 promotes the proliferation of HSCs.
Fig. 4: CDK19 deficiency impairs the proliferation and hematopoietic repopulation ability of HSCs in a cell-intrinsic manner.
Fig. 5: CDK19 regulates the cell cycle profile of HSCs.
Fig. 6: CDK19 inhibits the expression of p21 via a p53-dependent mechanism.
Fig. 7: p53 inhibitor treatment rescues the impaired phenotype and function of CDK19−/− HSCs.
Fig. 8: SenexinB treatment potently attenuates the proliferation of AML cells.

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Acknowledgements

The authors thank Jinyong Wang for gifting the CD45.1 mice, Yang Liu and Haiying Ran for technical support in flow cytometry. This work was supported by grants from the National Natural Science Fund of China (No. 81930090, 81725019) and the Scientific Research Project of PLA (AWS16J014).

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ZZ and YL performed experiments, analyzed data, and wrote the manuscript; YQ and YX contributed to animal experiments and data analysis; SW, FC, MS and MC contributed to flow cytometric analysis; NC, LY and SC contributed to the in vitro experiments; FW and YS contributed to the initial experimental design and discussed the manuscript; MH and JW conceived and supervised the study, analyzed the data, and wrote and revised the manuscript. All the authors read and approved the final manuscript.

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Correspondence to Mengjia Hu or Junping Wang.

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Zhang, Z., Lu, Y., Qi, Y. et al. CDK19 regulates the proliferation of hematopoietic stem cells and acute myeloid leukemia cells by suppressing p53-mediated transcription of p21. Leukemia 36, 956–969 (2022). https://doi.org/10.1038/s41375-022-01512-5

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