Epigenetic inactivation of the CIP/KIP cell-cycle control pathway in acute leukemias

Abstract

Dysregulation of the cell cycle is important in oncogenesis. We analyzed the potential inactivation of the CIP/KIP family of the cyclin E/CDK/RB pathway by gene promoter hypermethylation in leukemias. The methylation-specific polymerase chain reaction (MSP) with primers for methylated (M-MSP) and unmethylated (U-MSP) alleles of the p21, p27, and p57 genes was used to study five leukemic cell lines, 50 acute myeloid leukemia (AML) samples, and 25 acute lymphoblastic leukemia (ALL) samples. p21 was hemizygously methylated in Raji and Jurkat but remained unmethylated in U937, HL60, and NB4. p27 was hemizygously methylated in Raji but unmethylated in the other cell lines. p57 was completely methylated in Raji and NB4, hemizygously methylated in U937, and unmethylated in HL60 and Jurkat. At diagnosis, p21 methylation was not detected in any case of AML or ALL. p27 methylation occurred in 2 (4%) AML patients and in 1 (4%) ALL patient. p57 methylation occurred in 1 (2%) AML patient and in 1 (4%) ALL patient. Therefore, methylation inactivation of the INK4/CDK/RB pathway in leukemia is infrequent. A review of the literature showed a marked variation in the frequencies of methylation of these genes, which might be attributable to difference in methodologies used to detect gene methylation. Am.

The Cdk inhibitor p57Kip2 controls LIM-kinase 1 activity and regulates actin cytoskeleton dynamics

“…Decreased expression of p57 Kip2 has been found frequently in human cancer cells, mainly due to silencing of the gene by different epigenetic changes (Shin et al, 2000;Kobatake et al, 2004;Chim et al, 2005). Several studies have correlated poor patient outcomes with loss or low levels of p57…”

“…In particular, members of the cyclin-Cdk inhibitors of the Cip/Kip family, composed of p21 other cell-cycle inhibitors cannot compensate for (Yan et al, 1997;Zhang et al, 1997). In addition, the p57 Kip2 gene, located on chromosome 11p15.5, has been suggested to be a tumor suppressor gene, being inactivated in various types of human cancers (Shin et al, 2000;Nakai et al, 2002;Sui et al, 2002;Li et al, 2003;Kobatake et al, 2004;Chim et al, 2005). In fact, loss or low levels of p57…”

The cell cycle inhibitor p57Kip2 promotes cell death via the mitochondrial apoptotic pathway

“…Accordingly, inactivation of p57 Kip2 by regional promoter hypermethylation and histone deacetylation has been suggested in human tumors. 25,26 Finally, several apoptotic stimuli, including treatment with hypomethylating agents, histone deacetylase inhibitors 27 or p73beta overexpression 28 have been shown to induce p57 Kip2 expression. In the case of p73beta-mediated apoptosis, silencing p57 Kip2 considerably reduced cell death, suggesting that p57 Kip2 was required.…”

p57Kip2 and Cancer: Time for a Critical Appraisal

“…Brakensiek and colleagues (141) reported the absence of CDKN1C methylation in myelodysplastic syndrome and acute myeloid leukemia (AML). A subsequent analysis of CDKN1C methylation in 50 AML and 25 ALL patients identified only 2 cases of AML and 1 ALL case with hypermethylated CDKN1C (142). Similarly, only 4 cases out of 56 newly diagnosed patients with chronic lymphocytic leukemias showed CDKN1C hypermethylation (143).…”