Regulation of the hematopoietic stem/progenitor cell subsets in mouse bone marrow by the cdk inhibitor p18INK4c

Although the majority of hematopoietic stem cells (HSC) is quiescent in adult mouse bone marrow, all HSC are recruited into cycle regularly. Thus, HSC repeatedly enter and exit the cell cycle. Activation of quiescent cells requires D type cyclins in association with cyclin-dependent kinase (CDK) 4/6. The CDK inhibitor p18INK4c, which binds to CDK4/6 to block its association with cyclin D, is expressed in hematolymphoid organs and implicated in modulating hematopoiesis. In p18 null mouse bone marrow, we observed a significant increase of the newly described HSC subset (Lin- Sca+ c-Kit-) cells, and a relative decrease in the Lin-Sca+ c-Kit+ HSC cells. The p18 null Lin-Sca+c-Kit+ cells, however, are hyperproliferative in response to c-Kit ligand (KL) and IL6. The p18 null, as well as wild type, Lin-Sca+c-Kit- cells show no proliferative activity in response to IL6 and KL. Therefore, p18INK4c is involved in regulating proliferation of Lin-Sca+c-Kit+ HSC cells and in generation of Lin-Sca+c-Kit- HSPC in the bone marrow.