CITED2 coordinates key hematopoietic regulatory pathways to maintain the HSC pool in both steady-state hematopoiesis and transplantation

Stem Cell Reports. 2021 Nov 9;16(11):2784-2797. doi: 10.1016/j.stemcr.2021.10.001. Epub 2021 Oct 28.


Hematopoietic stem cells (HSCs) reside at the apex of the hematopoietic differentiation hierarchy and sustain multilineage hematopoiesis. Here, we show that the transcriptional regulator CITED2 is essential for life-long HSC maintenance. While hematopoietic-specific Cited2 deletion has a minor impact on steady-state hematopoiesis, Cited2-deficient HSCs are severely depleted in young mice and fail to expand upon aging. Moreover, although they home normally to the bone marrow, they fail to reconstitute hematopoiesis upon transplantation. Mechanistically, CITED2 is required for expression of key HSC regulators, including GATA2, MCL-1, and PTEN. Hematopoietic-specific expression of anti-apoptotic MCL-1 partially rescues the Cited2-deficient HSC pool and restores their reconstitution potential. To interrogate the Cited2→Pten pathway in HSCs, we generated Cited2;Pten compound heterozygous mice, which had a decreased number of HSCs that failed to reconstitute the HSC compartment. In addition, CITED2 represses multiple pathways whose elevated activity causes HSC exhaustion. Thus, CITED2 promotes pathways necessary for HSC maintenance and suppresses those detrimental to HSC integrity.

Keywords: CITED2; MCL-1; PTEN; hematopoiesis; hematopoietic stem cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Cell Proliferation / genetics
  • Gene Expression Regulation*
  • Gene Regulatory Networks / genetics
  • Hematopoiesis / genetics*
  • Hematopoietic Stem Cell Transplantation / methods*
  • Hematopoietic Stem Cells / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • RNA-Seq / methods
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / genetics
  • Time Factors
  • Trans-Activators / genetics*
  • Trans-Activators / metabolism


  • Cited2 protein, mouse
  • Repressor Proteins
  • Trans-Activators