Cyclin-dependent kinase inhibitors (CKIs) and hematological malignancies

Abstract

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-CDK6 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 TGFß, seems to be a mediator of TGFß-mediated cell cycle arrest. Furthermore, p18^Ink4c inhibits CDK6 phosphorylation and activation by CAK. The second CKIs family is constituted by p21^Waf1, 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^Ink4d, p27^Kip1 causes late G1 cell cycle arrest after TGFß 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.