Role of Cks1 for l-dependent and -indepentend cell cycle regulation, survival and quiescence in normal and leukemic hematopoiesis

• Applicant: Professor Dr. Ulrich Keller
• Subject Area: Hematology, Oncology
• Term: from 2012 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 223306220

The cyclin-dependent kinase inhibitors (CKI) p27Kip1 and p21Cip1 have been shown to regulate the size, quality and repopulation efficiency of the hematopoietic stem/ progenitor cell (HSC/ HPC) pool. Both p27Kip1 and p21Cip1 are targets of the E3 ubiquitin ligase SCFSkp2/Cks1 that controls their protein levels to regulate G1-S transition, S phase progression and G2-M transition. In the absence of the essential SCFSkp2 component Cyclin-dependent kinase subunit 1 (Cks1) p27Kip1 and p21Cip1 protein accumulate. Preliminary results indicate that Cks1 is highly expressed in early HSC and that loss of Cks1 results in Cks1 in normal and malignant hematopoiesis a depletion of the HSC/HPC pool. Furthermore, our preliminary data indicate that Cks1 protects early hematopoietic cells from apoptosis. To test the hypothesis that Cks1, either CKI-dependent via SCFSkp2/Cks1, or independent of CKI, regulates HSC homeostasis, we will generate mutant mice that lack Cks1 and p27Kip1 (Cks1-/-;p27-/-), and mice that lack Cks1 and p21Cip1 (Cks1-/-;p21-/-), as well as required compound knock-out mice. Normal and challenged hematopoiesis will be evaluated. Bone marrow from these compound mice and from control mice will be infected with retrovirus encoding Bcr- Abl and then transplanted into wild type recipient mice to induce a myeloproliferative disorder/CML-like disease and the stem cell pool will be analyzed. Our hypothesis is that Cks1 regulates the normal and malignant hematopoietic stem cell pool. The proposed experiments will allow addressing the role and mechanism of Cks1 in steady state and challenged hematopoiesis with regard to proliferation, self renewal, survival, and differentiation.

• DFG Programme: Research Grants
• Participating Person: Professor Dr. Nikolas von Bubnoff