An intimate relationship exists between cell cycle regulation and hematopoietic progenitor and stem cell function. While p21WAF/CIP1 controls normal murine hematopoietic stem cell quiescence, p27KIP1 regulates the pool of more mature progenitors. Little is known of the function performed by other cyclin dependent kinase inhibitors (CDKI) in primary hematopoietic cells. Using CD34-positive, primary, human hematopoietic progenitor/stem cells, we have identified p57KIP2 as the only CDKI rapidly and robustly upregulated by transforming growth factor beta (TGFbeta). We have shown that this regulation is transcriptional and is mediated through the proximal p57KIP2 promoter. The upregulation of p57KIP2 is essential for TGFbeta-induced growth arrest in these cells as two different siRNAs (small interfering RNA) that block p57KIP2 upregulation block the growth inhibitory effects of TGFb on human hematopoietic cells. Reduction of p57 KIP2 expression also allows hematopoietic cells to proliferate more readily in the absence of TGFbeta, TGFbeta has pleiotropic effects on diverse cell types and tissues and dysregulated TGFbeta signal transduction is an important, and common, property of malignant cells. Whereas primary cultures of normal cells are highly sensitive to growth-inhibition by TGFbeta, most malignant cells and leukemia-derived cell lines are resistant to this effect. Despite the frequency with which mutations in the TGFbeta signaling pathway arise in solid tumors, they are exceedingly uncommon in leukemias suggesting that other mechanisms dysregulate this pathway in the hematopoietic malignancies. In this light, it may be significant that p57KIP2 is silenced in 30% of de novo AML cases. Based upon our findings, we hypothesize that p57KIP2 plays a major role in the maintenance of stem cell quiescence and in restraining progenitor expansion. To test this hypothesis we propose the following: 1) To define the role of p57KIP2 in normal hematopoietic progenitor/stem cell proliferation, differentiation and self-renewal; 2) To determine the mechanism by which TGFb upregulates the transcription of p57KIP2 in hematopoietic cells; and 3) To assess the tumor-suppressor activity of p57KIP2 in hematopoietic malignancies.
|Brenet, Fabienne; Kermani, Pouneh; Spektor, Roman et al. (2013) TGF? restores hematopoietic homeostasis after myelosuppressive chemotherapy. J Exp Med 210:623-39|