Discovery of epigenetically silenced genes in acute myeloid leukemias

Abstract

The demethylating 5-aza-2 0 deoxycytidine (DAC) and the histone deacetylase inhibitor (HDACi) suberoyl anilide bishydroxamide (SAHA) possess potent antitumorigenic properties in myeloid disorders. However, the transcriptome alterations mediated by these drugs are poorly understood. We analyzed the transcriptional effects of DAC and SAHA in the AML cell line KG-1. Microarray analyses revealed 76 genes expressed in normal CD34 þ cells, absent in KG-1 cells but whose expression was induced after drug treatment. A total of 39 of these genes harbored CpG islands in their promoters. We examined the expression level of these genes in 120 AML patient samples representing diverse karyotpyes. Gas2l1, tfIIs, ehd3, enolase 2, mx1, dral, astml and pxdn were diminished across all AML karyotypes examined. Ehd3 was methylated in 63% of AML patients examined. This methylation was lost upon complete remission, and not observed in normal CD34 þ cells. CD34 þ cells expressed ehd3 at approximately 10-fold higher levels than AML samples. Another highlighted gene, a-catenin, is located at q31 of chromosome 5. Analyses of 29 5q-AML/ myelodysplastic syndrome (MDS) samples revealed marked decreases in expression of a-catenin, compared to non-5q-MDS samples (6.679-fold). However, no methylation was detected, suggesting indirect effects of these drugs on the expression of a-catenin.

Dependence receptors: a new paradigm in cell signaling and cancer therapy

“…DRAL was initially characterized as a downregulated gene in rhabdomyosarcoma (Genini et al, 1997). Low or no transcript levels were observed in lymphoblastic leukemia, promyelocytic leukemia and Burkitt's lymphoma cells (Johannessen et al, 2006;Desmond et al, 2007). Finally, caspase 8 expression is selectively lost during establishment of neuroblastoma metastases, rendering these cells refractory to unligated integrin-mediated cell death (Stupack et al, 2006).…”

5q– myelodysplastic syndromes: chromosome 5q genes direct a tumor-suppression network sensing actin dynamics

“…Diminished (or complete loss of) a-catenin expression is observed in a host of primary cancers (for example, breast, colorectal, prostate), as well as in cancer cell lines derived from primary tumors (for example, leukemia, leukocyte, colon, prostate) (Benjamin and Nelson, 2008). Furthermore, human samples from MDS patients revealed a loss of a-catenin protein expression within myeloid progenitor cells (Desmond et al, 2007;Liu et al, 2007), and, in some cancers, diminished a-catenin is a strong predictor of invasive and metastatic behaviors, increased survival and proliferation.…”

Reprogramming epigenetic silencing: artificial transcription factors synergize with chromatin remodeling drugs to reactivate the tumor suppressor mammary serine protease inhibitor

“…Unlike real-time, which specifically measures maspin mRNA levels, cell viability is a complex phenotype involving many different gene products, including tumor suppressors such as maspin. The higher effect of SAHA and 5-aza-2 ¶-dC observed in viability assays might suggest that these compounds reactivate many tumor suppressor genes, not just maspin (46,47). Although off-target effects are possible with ATFs, these proteins have been engineered to reactivate specifically maspin and are not expected to regulate other tumor suppressor genes.…”