Transcription factor PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress

Chavez, J. S.; Rabe, J. L.; Loeffler, D.; Higa, K.; Hernandez, G.; Mills, T. S.; Ahmed, N.; Gessner, R. L.; Ke, Z.; Idler, B. M.; Kim, H. M.; Myers, J. R.; Stevens, B. M.; Jordan, C. T.; Nakajima, H.; Ashton, J.; Welner, R. S.; Schroeder, T.; DeGregori, J.; Pietras, E. M.

doi:10.1101/2020.05.18.102830

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bioRxiv · 10.1101/2020.05.18.102830

Transcription factor PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress

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Abstract

Loss of hematopoietic stem cell (HSC) quiescence and resulting clonal expansion are common initiating events in the development of hematological malignancy. Likewise, chronic inflammation related to aging, disease and/or tissue damage is associated with leukemia progression, though its role in oncogenesis is not clearly defined. Here, we show that PU.1-dependent repression of protein synthesis and cell cycle genes in HSC enforces homeostatic protein synthesis levels and HSC quiescence in response to IL-1 stimulation. These genes are constitutively de-repressed in PU.1-deficient HSC, leading to activation of protein synthesis, loss of quiescence and aberrant expansion of HSC. Taken together, our data identify a mechanism whereby HSC regulate their cell cycle activity and pool size in response to chronic inflammatory stress.

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Chavez, J. S., Rabe, J. L., Loeffler, D., Higa, K., Hernandez, G., Mills, T. S., Ahmed, N., Gessner, R. L., Ke, Z., Idler, B. M., Kim, H. M., Myers, J. R., Stevens, B. M., Jordan, C. T., Nakajima, H., Ashton, J., Welner, R. S., Schroeder, T., DeGregori, J., Pietras, E. M.. 2020-05-20. Transcription factor PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress. https://doi.org/10.1101/2020.05.18.102830

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