Table 1 A summary of phenotypes observed following deletion of cell cycle regulating genes
From: Promiscuous and lineage-specific roles of cell cycle regulators in haematopoiesis
Gene deletion | Expression in haematopoieitc system | Haematopoietic system | Other phenotypes |
|---|---|---|---|
Cyclin D1 | Unexpressed in the majority of haematopoietic lineages | No overt haematopoietic phenotype | Developmental neurological abnormalities; hypoplastic retina; impaired Schwann cell regeneration |
Cyclin D2 | Expression in majority of haematopoietic cell types; absent in small pre-B cells | Abnormal B-lymphocytes: impaired proliferation; hypo-responsive to BCR and mitogenic stimulation; impaired CD5 B cell development; immunodeficiency in IgG3 and IgA | Sterility in females, cerebellar abnormalities, hypoplastic testes in males; cerebellar abnoralities; reduced susceptability to specifc cancers |
Cyclin D3 | Expression in majority of haematopoietic cell types | Depletion of small pre-B cells; impaired thymic T cell development; impaired maturation of granulocytes in the bone marrow; reduced levels of circulating neutrophil granulocytes | Resistant to Notch-driven leukaemias |
Cyclin D2; Cyclin D3 | Upregulation of cyclin D3 in cyclin D2 null B cells; ubiquitous upregulaion of wild-type cyclin in single deletion embryos | As single deletions with severe megaloblastic anemia | Embryonic lethal at late developmental stages |
CDK2 | Expression in majority of haematopoietic cell types | No overt haematopoietic phenotype | Reduced body size; infertility |
CDK4 | Expression in majority of haematopoietic cell types | No overt haematopoietic phenotype | Dwarfism-like phenotype; infertility; hypocellularity in many organs; diabetes |
CDK6 | Expression in majority of haematopoietic cell types | Mild haematopoietic defects: hypoplasia of thymuses and spleens; delayed G1 progression in lymphocytes; depletion of megakaryocytes and erythrocytes | No overt phenotype |
CDK2; CDK4 | As above | Severe haematopoietic defects: reduced proliferation of multipotential progenitors; decrease in cellularity of all haematopoietic subpopulations | Embryonic lethality due to heart defects |
CDK4; CDK6 | As above | Multi-lineage haematopoietic abnormalities: reduction in cellularity of lymphoid, myeloid and granulocyte-macrophage progenitors; loss of mature haematopoietic cells | Late-stage embryonic lethal; anaemia |
p15INK4b | Absent in HSC; increases in myeloid and lymphoid lineages | No overt haematopoietic phenotype | No overt phenotype |
p16INK4a | Highly expressed in HSC; down-regulated with differentiation of all lineages | No overt haematopoietic phenotype; increased ability for clonal expansion of haematopoetic progenitor cells; long latency B-cell lymphomas | No overt phenotype |
p18INK4c | Higher levels in HSC compared with more mature myeloid and lymphoid cells | Hyperplastic spleen and thymus; increased cellularity and hypersensitivity of T and B-cell lymphocytes to mitogenic stimulation; T-cell lymphoma | Widespread hyperplasia and organomegaly |
p19INK4d | Higher levels in HSC compared with more mature myeloid and lymphoid cells | No overt haematopoietic phenotype | No overt phenotype |
p21Cip1 | Variable | Increase in HSC cycling; reduced progenitor cell replication; decrease of circulating inflammatory monocytes in peripheral blood | No overt phenotype |
p27Kip1 | Variable | Increased progenitor cell activity; hyperplasia observed in most haematopoietic organs, particularly pronounced in the thymus and spleen | Multiple organ hyperplasia |
p57Kip2 | Induced by TGF-β in specific progenitor/HSC (CB-CD34) | No overt haematopoietic phenotype | No overt phenotype |