Cell cycle regulation in HSCs and MPN SCs. Progression through the G₁ checkpoint into S phase is regulated by the retinoblastoma protein (Rb), whose activity is controlled via phosphorylation by cyclin dependent kinases (CDKs) that are activated by D cyclins, and negatively regulated by CDK inhibitors. Total CDK activity rather than substrate specificity orderly drives the cell cycle progression.⁶⁵ In HSCs, this critical system is tightly regulated, with redundant checks and balances. For instance, cell cycle entry is normal in p57 (Cdkn1c)^−/− HSCs because of compensatory upregulation of p27. However, HSCs null for both p57 and p27 show increased proliferation and reduced engraftment when transplanted. Mechanistically, Hsp70 interacts with cytoplasmic p57 and p27. Combined deletion of p57 and p27 from HSCs results in nuclear translocation of an Hsp70/cyclin D1 complex that promotes Rb phosphorylation.⁶⁶ The role of specific cell cycle regulators varies between mouse strains. For instance, p21 (Cdkn2a) deletion causes hematopoietic failure in serial transplantation in 129/Sv, but not in C57BL/6 mice, unless the latter are irradiated.^67,68