Cyclin-dependent kinase inhibitors (CKIs) and hematological malignancies

Cell proliferation control is ensured by a group of proteins named cyclin-dependent kinases (CDKs), the activation of which is dependent on phosphorylation and cyclin association. In parallel, these CDKs are negatively controlled by two distinct groups of inhibitory proteins, the cyclin-dependent kinase inhibitors (CKIs). The first group, including p16(INk4a), p15(Ink4b) p18(Ink4c) and p19(Ink4d), is specific for the G1 CDKs, CDK4 and CDK6, inhibiting the kinase activity of cyclin D/CDK4-CDKG complexes on pRb. p16(Ink4a), down-regulated by pRb, inhibits G1 CDKs by competition with cyclin D; p15(Ink4b), the synthesis of which is induced by TGF beta, seems to be a mediator of TGF beta-mediated cell cycle arrest. Furthermore, p18(Ink4c) inhibits CDK6 phosphorylation and activation by CAK. The second CKIs family is constituted by p(21Waf1), p27(Kip1) and p57(Kip2). Their inhibitory action concerns a large range of cyclin/CDK complexes involved in G1 and S phase. p21(Waf1), induced in part by p53, is up-regulated by senescence, DNA damage and cellular differentiation. p21(Waf1) forms quaternary complexes with CDKs, cyclins and PCNA. Its inhibitory action, preventing CDK from phosphorylation, depends on the stoichiometry of the components. As p15(Ink4b), p27(Kip1) causes late G1 cell cycle arrest after TGF beta treatment and contact inhibition. The implications of CKIs in hematological malignancies are function of deletions or mutations of their genes. p16(Ink4a) and p15(Ink4b) genes, localized on 9p21, present frequent homozygous deletions in ALL T, ATL and lymphoblastic acutisation of CML. The other CKIs present very rare homozygous deletions or mutations, particularly p21(Waf1) and p27(Kip2). However, reduction of inhibitory activity due to hemizygous deletions might favour leukemogenesis.