RUNX1 overexpression triggers TGF-β signaling to upregulate p15 and thereby blocks early hematopoiesis by inducing cell cycle arrest

Stem Cell Res. 2022 Apr:60:102694. doi: 10.1016/j.scr.2022.102694. Epub 2022 Jan 31.

Abstract

p15INK4b (cyclin-dependent kinase inhibitor 2B, CDKN2B, p15), a cyclin-dependent kinase inhibitor (CKI) belonging to the INK4 family, plays an important role in hematopoiesis. Its expression level was positively related to the blockage effects of RUNX1b at the early stage. Experiments using human embryonic stem cell (hESC) lines with inducible p15 expression suggested that p15 overexpression can significantly decrease the proportion of KDR+ cells in S and G2-M stages 4 days after induction from day 0. Moreover, p15 overexpression from the early stage can decrease production of CD34highCD43- cells and their derivative populations, but not CD34lowCD43- cells. These effects were weakened if induction was delayed and disappeared if induction started after day 6. All these effects were counteracted by inhibition of TGF-β signaling. TGF-β1 stimulation elicited similar effects as p15 overexpression. RUNX1 overexpression and activation of the TGF-β signaling pathway upregulate the expression of p15, which is partially responsible for blockade of hematopoiesis and relevant to a change in the cell cycle status. However, it is possible that other mechanisms are involved in the regulation of hematopoiesis.

Keywords: Cell cycle; Hematopoiesis; Human embryonic stem cell (hESC); P15; RUNX1/AML1; TGF-β signaling pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle
  • Cell Cycle Checkpoints
  • Cell Cycle Proteins*
  • Core Binding Factor Alpha 2 Subunit* / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Hematopoiesis
  • Humans
  • Transforming Growth Factor beta / metabolism
  • Tumor Suppressor Proteins

Substances

  • Cell Cycle Proteins
  • Core Binding Factor Alpha 2 Subunit
  • Cyclin-Dependent Kinase Inhibitor p16
  • RUNX1 protein, human
  • Transforming Growth Factor beta
  • Tumor Suppressor Proteins