Cyclin A2 Plays a Critical Role Not Only in Self-Renewal of Hematopoietic Stem Cells, but Also in Non-Self-Renewing Proliferation of Lymphoid Progenitors.

Abstract 381

Cyclins are regulatory subunits of cyclin-dependent kinase, and are important components of cell cycle engine. The A-type cyclin is generally the S-phase cyclin. Mammalian cells express two A-type cyclins, including cyclin A1 that is exclusively expressed in the testis, and cyclin A2 whose expression is ubiquitous. We have recently reported that cyclin A2 is not required for fibroblast proliferation but it is indispensable in maintenance of self-renewal of stem cells, including embryonic stem cells and hematopoietic stem cells (HSCs) (Cell 138 2009). The question is whether cyclin A2 plays a role in proliferation of hematopoietic progenitors downstream of the HSC. Here we further assessed the requirement of A-type cyclin in non-self-renewing hematopoietic progenitors. Quantitative RT-PCR analysis showed that cyclin A2 was expressed in hematopoietic stem and progenitor cells, but its expression level is highest in lymphoid-committed progenitor stages of both T and B cell lineages. Thus, in order to test the role of cylin A2 in early lymphopoiesis, we crossed cyclin A2 floxed mice with Rag1-Cre knock-in mice. Rag1 expression is initiated at the preproB to the proB stages, and the DN1-DN3 stages in the thymus, while their proliferation is dependent at least upon pre-BCR or pre-TCR signal at these stages. Interestingly, the Rag1-Cre cyclin A2 floxed/floxed mice were viable, and have normal numbers of HSCs and myeloid progenitors in the bone marrow. They, however, displayed severe reduction of T and B cell numbers that were only 1/100 - 1/10 of wild-type controls; the number of common lymphoid progenitor was unchanged, but there were almost complete loss of proB and preB cells. Similarly, all thymic T cell progenitor compartments such as CD4-CD8- double negative, and CD4+CD8+ double positive populations were severely reduced. These findings clearly demonstrate that cyclin A2 is indispensable not only for self-renewal of HSCs, but also for proliferation of T and B cell progenitors.