title: Hematopoiesis specific loss of Cdk2 and Cdk4 results in increased erythrocyte size and delayed platelet recovery following stress.
abstract: Mouse knockouts of Cdk2 and Cdk4 are individually viable whereas the double knockouts are embryonic lethal due to heart defects, and this precludes the investigation of their overlapping roles in definitive hematopoiesis. Here we use a conditional knockout mouse model to investigate the effect of combined loss of Cdk2 and Cdk4 in hematopoietic cells. Cdk2(fl/fl)Cdk4(-/-)vavCre mice are viable but displayed a significant increase in erythrocyte size. Cdk2(fl/fl)Cdk4(-/-)vavCre mouse bone marrow exhibited reduced phosphorylation of the retinoblastoma protein and reduced expression of E2F target genes such as cyclin A2 and Cdk1. Erythroblasts lacking Cdk2 and Cdk4 displayed a lengthened G1 phase due to impaired phosphorylation of the retinoblastoma protein. Deletion of the retinoblastoma protein rescued the increased size displayed by erythrocytes lacking Cdk2 and Cdk4, indicating that the retinoblastoma/Cdk2/Cdk4 pathway regulates erythrocyte size. The recovery of platelet counts following a 5-fluorouracil challenge was delayed in Cdk2(fl/fl)Cdk4(-/-)vavCre mice revealing a critical role for Cdk2 and Cdk4 in stress hematopoiesis. Our data indicate that Cdk2 and Cdk4 play important overlapping roles in homeostatic and stress hematopoiesis, which need to be considered when using broad-spectrum cyclin-dependent kinase inhibitors for cancer therapy.
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR Agency for Science, Technology and Research, Republic of Singapore.
authors.forename: Senthil Raja
authors.initials: SR
authors.lastname: Jayapal
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR Agency for Science, Technology and Research, Republic of Singapore Cancer Science Institute of Singapore, National University of Singapore, Republic of Singapore.
authors.forename: Chelsia Qiuxia
authors.initials: CQ
authors.lastname: Wang
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR Agency for Science, Technology and Research, Republic of Singapore.
authors.forename: Xavier
authors.initials: X
authors.lastname: Bisteau
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR Agency for Science, Technology and Research, Republic of Singapore National University of Singapore, Department of Biochemistry, Republic of Singapore.
authors.forename: Matias J
authors.initials: MJ
authors.lastname: Caldez
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR Agency for Science, Technology and Research, Republic of Singapore.
authors.forename: Shuhui
authors.initials: S
authors.lastname: Lim
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR Agency for Science, Technology and Research, Republic of Singapore.
authors.forename: Vinay
authors.initials: V
authors.lastname: Tergaonkar
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Republic of Singapore.
authors.forename: Motomi
authors.initials: M
authors.lastname: Osato
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR Agency for Science, Technology and Research, Republic of Singapore National University of Singapore, Department of Biochemistry, Republic of Singapore kaldis@imcb.a-star.edu.sg.
authors.forename: Philipp
authors.initials: P
authors.lastname: Kaldis
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D048429:Cell Size; D051357:Cyclin-Dependent Kinase 2 / Q000172:deficiency / Q000235:genetics*; D051358:Cyclin-Dependent Kinase 4 / Q000172:deficiency / Q000235:genetics; D004912:Erythrocytes / Q000166:cytology*; D005260:Female; D017353:Gene Deletion; D006400:Hematocrit; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D016130:Immunophenotyping; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D011003:Ploidies; D016160:Retinoblastoma Protein / Q000235:genetics; D013312:Stress, Physiological
chemical_list: D016160:Retinoblastoma Protein; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4