104 research outputs found
DNA methylation of enhancer elements in myeloid neoplasms: think outside the promoters?
Gene regulation through DNA methylation is a well described phenomenon that has a
prominent role in physiological and pathological cell-states. This epigenetic modification is usually
grouped in regions denominated CpG islands, which frequently co-localize with gene promoters,
silencing the transcription of those genes. Recent genome-wide DNA methylation studies have
challenged this paradigm, demonstrating that DNA methylation of regulatory regions outside
promoters is able to influence cell-type specific gene expression programs under physiologic or
pathologic conditions. Coupling genome-wide DNA methylation assays with histone mark annotation
has allowed for the identification of specific epigenomic changes that affect enhancer regulatory
regions, revealing an additional layer of complexity to the epigenetic regulation of gene expression.
In this review, we summarize the novel evidence for the molecular and biological regulation of
DNA methylation in enhancer regions and the dynamism of these changes contributing to the
fine-tuning of gene expression. We also analyze the contribution of enhancer DNA methylation on the
expression of relevant genes in acute myeloid leukemia and chronic myeloproliferative neoplasms.
The characterization of the aberrant enhancer DNA methylation provides not only a novel pathogenic
mechanism for different tumors but also highlights novel potential therapeutic targets for myeloid
derived neoplasms
HDAC inhibitors in acute myeloid leukemia
Acute myeloid leukemia (AML) is a hematological malignancy characterized by uncontrolled
proliferation, differentiation arrest, and accumulation of immature myeloid progenitors. Although
clinical advances in AML have been made, especially in young patients, long-term disease-free
survival remains poor, making this disease an unmet therapeutic challenge. Epigenetic alterations
and mutations in epigenetic regulators contribute to the pathogenesis of AML, supporting the
rationale for the use of epigenetic drugs in patients with AML. While hypomethylating agents have
already been approved in AML, the use of other epigenetic inhibitors, such as histone deacetylases
(HDAC) inhibitors (HDACi), is under clinical development. HDACi such as Panobinostat, Vorinostat,
and Tricostatin A have been shown to promote cell death, autophagy, apoptosis, or growth arrest in
preclinical AML models, yet these inhibitors do not seem to be effective as monotherapies, but rather
in combination with other drugs. In this review, we discuss the rationale for the use of different
HDACi in patients with AML, the results of preclinical studies, and the results obtained in clinical
trials. Although so far the results with HDACi in clinical trials in AML have been modest, there are
some encouraging data from treatment with the HDACi Pracinostat in combination with DNA
demethylating agents
p53 Aberrations do not predict individual response to fludarabine in patients with B-cell chronic lymphocytic leukaemia in advanced stages Rai III/IV
Abnormalities of p53 have been associated with short survival and non-response to therapy in chronic lymphocytic leukaemia (CLL). We have evaluated the rate of response to fludarabine as first-line therapy in 54 patients with advanced stage CLL, analysing the cytogenetic profile, aberrations in p53, including the methylation status of its promoter, and the immunoglobulin heavy-chain variable-region (IGVH) mutation status. According to the advanced stage of the disease in this series, 75% of patients presented genetic aberrations associated with poor prognosis: del(17p) and/or del(11q), and no-mutated IGVH genes. Ten patients (18.5%) had methylation in the promoter region of p53. Eighty-three per cent of patients treated achieved a response, with a high rate of complete remission (47.6%). Although we found a significant correlation between failures and the presence of p53 aberrations (P = 0.0065), either with methylation (P = 0.018) or deletion (P = 0.015), 64% of the patients with aberrations in this gene responded to treatment (11/17), suggesting that fludarabine induces high remission rates, even in these patients. This is the first time that the significance of p53 promoter methylation status is described in this pathology, and our data support that this epigenetic phenomenon could be involved in the pathogenesis and clinical evolution of CLL
Epigenetic modifiers: anti-neoplastic drugs with immunomodulating potential
Cancer cells are under the surveillance of the host immune system. Nevertheless, a number of immunosuppressive mechanisms allow tumors to escape protective responses and impose immune tolerance. Epigenetic alterations are central to cancer cell biology and cancer immune evasion. Accordingly, epigenetic modulating agents (EMAs) are being exploited as anti-neoplastic and immunomodulatory agents to restore immunological fitness. By simultaneously acting on cancer cells, e.g. by changing expression of tumor antigens, immune checkpoints, chemokines or innate defense pathways, and on immune cells, e.g. by remodeling the tumor stroma or enhancing effector cell functionality, EMAs can indeed overcome peripheral tolerance to transformed cells. Therefore, combinations of EMAs with chemo- or immunotherapy have become interesting strategies to fight cancer. Here we review several examples of epigenetic changes critical for immune cell functions and tumor-immune evasion and of the use of EMAs in promoting anti-tumor immunity. Finally, we provide our perspective on how EMAs could represent a game changer for combinatorial therapies and the clinical management of cancer
Transcriptional silencing of the Dickkopfs-3 (Dkk-3) gene by CpG hypermethylation in acute lymphoblastic leukaemia
Dkk-3 is a newly characterised mortalisation-related gene and an antagonist of the Wnt oncogenic signalling pathway whose
expression is decreased in a variety of cancer cell lines, suggesting that the Dkk-3 gene, located at chromosome 11p15.1, functions as
a tumour suppressor gene. Although 11p15 is a ‘hot spot’ for methylation in acute lymphoblastic leukaemia (ALL), the role of Dkk-3
abnormalities has never been evaluated in this disease. We analysed CpG island methylation of the Dkk-3 promoter in six ALL cell
lines and 183 ALL patients. We observed Dkk-3 hypermethylation in all cell lines and in cells from 33% (60/183) of ALL patients.
Moreover, Dkk-3 methylation was associated with decreased Dkk-3 mRNA expression and this expression was restored after
exposure to the demethylating agent 5-AzaC. Clinical features did not differ between hypermethylated and unmethylated patients.
Estimated disease-free survival (DFS) and overall survival at 10 and 11 years, respectively, were 49.8 and 45.6% for normal patients
and 10.5 and 15.1% for hypermethylated patients (P¼0.001 and 0.09). Multivariate analysis demonstrated that Dkk-3 methylation
was an independent prognostic factor predicting DFS (P¼0.0009). Our data suggest that Dkk-3 methylation occurs at an early stage
in ALL pathogenesis and probably influences the clinical behaviour of the disease
Bortezomib decreases Rb phosphorylation and induces caspase-dependent apoptosis in Imatinib-sensitive and -resistant Bcr-Abl1-expressing cells
The use of c-abl-specific inhibitors such as Imatinib (IM)
or Dasatinib has revolutionized the treatment of chronic
myeloid leukemia (CML). However, a significant percentage
of patients become resistant to IM. In this report, we
have analyzed the possibility of using the proteasome as a
molecular target in CML. Our results show that cells that
express Bcr-Abl1 are more sensitive to the inhibition of
the proteasome with Bortezomib (Btz) than control cells.
This treatment reduces the proliferation of Bcr-Abl1-
expressing cells, by inactivating NF-jB2 and decreasing
the phosphorylation of Rb, eventually leading to an
increase in caspase-dependent apoptosis. Furthermore,
we show that Btz also induces cell-cycle arrest and
apoptosis in cells expressing Bcr-Abl1 mutants that are
resistant to IM. These results unravel a new molecular
target of Btz, that is the Rb pathway, and open new
possibilities in the treatment of CML especially for
patients that become resistant to IM because of the
presence of the T315I mutation
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