Induced cell-autonomous neutropenia systemically perturbs hematopoiesis in Cebpa enhancer-null mice

Roberto Avellino, Roger Mulet-Lazaro, Marije Havermans, Remco Hoogenboezem, Leonie Smeenk, Nathan Salomonis, Rebekka K. Schneider, Elwin Rombouts, Eric Bindels, Lee Grimes, Ruud Delwel*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)
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Abstract

The transcription factor C/EBPa initiates the neutrophil gene expression program in the bone marrow (BM). Knockouts of the Cebpa gene or its 137kb enhancer in mice show 2 major findings: (1) neutropenia in BM and blood; (2) decrease in long-term hematopoietic stem cell (LT-HSC) numbers. Whether the latter finding is cell-autonomous (intrinsic) to the LT-HSCs or an extrinsic event exerted on the stem cell compartment remained an open question. Flow cytometric analysis of the Cebpa 137kb enhancer knockout model revealed that the reduction in LT-HSC numbers observed was proportional to the degree of neutropenia. Single-cell transcriptomics of wild-type (WT) mouse BM showed that Cebpa is predominantly expressed in early myeloid-biased progenitors but not in LT-HSCs. These observations suggest that the negative effect on LT-HSCs is an extrinsic event caused by neutropenia. We transplanted whole BMs from 137kb enhancer-deleted mice and found that 40% of the recipient mice acquired full-blown neutropenia with severe dysplasia and a significant reduction in the total LT-HSC population. The other 60% showed initial signs of myeloid differentiation defects and dysplasia when they were sacrificed, suggesting they were in an early stage of the same pathological process. This phenotype was not seen in mice transplanted with WT BM. Altogether, these results indicate that Cebpa enhancer deletion causes cell-autonomous neutropenia, which reprograms and disturbs the quiescence of HSCs, leading to a systemic impairment of the hematopoietic process.

Original languageEnglish
Pages (from-to)1406-1419
Number of pages14
JournalBlood advances
Volume6
Issue number5
DOIs
Publication statusPublished - 8 Mar 2022

Bibliographical note

Acknowledgments:
The authors are grateful to Michael Vermeulen for the flow cytometric analysis and to their colleagues from the Erasmus Animal Facility, who took care of the mice used in this study and conducted regular bleeding to obtain blood cells. They would also like to thank Stefan Erkeland, Zhen Ping, and Jacqueline Feyen for their valuable input. The work was funded by grants and fellowships from the Dutch Cancer Society (EMCR 2015-7935) (R.D., R.A., R.M.L., M.H., and L.S.) and the Lady Tata Foundation (R.A.).

Publisher Copyright:
© 2022 by The American Society of Hematology.

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