Roles for the INK Family in Self Renewal of HSCs and as Tumor Suppressor Genes

In addition to p21 and p27, the INK4 family of CKIs is also implicated in the regulation of HSCs numbers and self-renewal. Mice deficient for p18 had an increased number of HSCs in the bone marrow. Also, competitive repopulation assays showed that p18- - HSCs were far more competitive than normal HSCs with 14-fold activities. In contrast to p21 HSCs, the exhaustion of p18- - HSCs was not observed during serial bone marrow transplants, indicating that p18 is a strong inhibitor limiting the potential of stem cell self-renewal in vivo [123]. From this result, it was speculated that downregulation of the expression of p18 in HSCs, using antisense oligonucleotide or small interfering RNA (siRNA), would be useful for the ex vivo expansion of HSCs.

p16 is highly expressed in CD34+ cells, and its expression is downregulated during differentiation process towards all lineages [124]. Nontheless, since p16- - mice did not show an apparent abnormality in hematopoiesis, p16 was supposed to be dispensable for the quiescence of HSCs [125,126]. However, Ito et al. found that p16 was essential for reconstitution activities of HSCs but not for proliferation or differentiation of progenitors from the analysis of mice lacking one of the cell cycle check point kinase, "ataxia telangiectasia mutated" (Atm) [127]. In this analysis, Atm-- mice older than 24 weeks developed progressive bone marrow failure due to a defect of HSC function, which was associated with elevated reactive oxygen species (ROS). Furthermore, they proved p16-retinoblastoma (Rb) pathway activated by ROS was critical for the defective function of HSCs. From these results, they concluded that the self-renewal ability of HSCs depend on ATM-mediated inhibition of oxidative stress and p16-RB pathway. Furthermore, Janzen et al. recently demonstrated that ageing causes an increase in p16 and intrinsic p16 suppress the proliferation of HSC/HPCs in the bone marrow. And they supposed that inhibition of p16 may ameliorate the physiological impact of ageing on stem cells and thereby improve injury repair in aged tissue [128].

In contrast to the expression pattern of p16, the expression of p15 is not detected in CD34+ cells, but increased specfically during myeloid differentiation [124,129]. However, the functional role of p15 in HSCs remained to be clarified. Both p16 and p15 inhibit the function of cyclin D-CDK4/6 complex and suppress the phosphorylation of pRb, thereby inducing cell cycle arrest at G0/G1 phase. Especially, under tumorgenetic stress such as the presence of oncogenic ras gene, p16 and p15 are induced to express and suppress tumor progression through the induction of premature senescence [130,131]. With these activities, both p16 and p15 are supposed to act as tumor suppressor genes. In fact, inactivation and/or deletion of p16 and p15 genes are observed in various human cancers very frequently [132,133]. As for hematological malignancies, their defects caused by the homozygous deletion or methylation were observed in a substantial proportion of AML, ALL, and myelodysplastic syndromes (MDS) cases [134-136]. These results indicate that appropriate cell cycle control, particularly at the stage of stem/progenitor cells, is required for maintaining normal hematopoiesis, and have to be uppermost when manipulating HSCs ex vivo.

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