The role of mutations in epigenetic regulators in myeloid malignancies

ArticleinNature Reviews Cancer 12(9):599-612 · August 2012with27 Reads
DOI: 10.1038/nrc3343 · Source: PubMed
Abstract
Recent genomic studies have identified novel recurrent somatic mutations in patients with myeloid malignancies, including myeloproliferative neoplasms (MPNs), myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). In some cases these mutations occur in genes with known roles in regulating chromatin and/or methylation states in haematopoietic progenitors, and in other cases genetic and functional studies have elucidated a role for specific mutations in altering epigenetic patterning in myeloid malignancies. In this Review we discuss recent genetic and functional data implicating mutations in epigenetic modifiers, including tet methylcytosine dioxygenase 2 (TET2), isocitrate dehydrogenase 1 (IDH1), IDH2, additional sex combs-like 1 (ASXL1), enhancer of zeste homologue 2 (EZH2) and DNA methyltransferase 3A (DNMT3A), in the pathogenesis of MPN, MDS and AML, and discuss how this knowledge is leading to novel clinical, biological and therapeutic insights.
    • "Interestingly, TET2 was mutated at a high frequency of 38 % (5/13) in ATL patients . These results are in line with the high rate of somatic TET2 inactivation observed in MDS, MPN, chronic myelomonocytic leukemia (CMML) and AML [28], and they suggest that TET2 may play an important role in ATL pathogenesis. TET2 LOH was found in two ATL patients with nonsense mutations at positions Q876* and Q414* (Fig.3a ), two mutations previously reported in CML patients. "
    [Show abstract] [Hide abstract] ABSTRACT: Epigenetic regulators play a critical role in the maintenance of specific chromatin domains in an active or repressed state. Disruption of epigenetic regulatory mechanisms is widespread in cancer cells and largely contributes to the transformation process through active repression of tumor suppressor genes. While mutations of epigenetic regulators have been reported in various lymphoid malignancies and solid cancers, mutation of these genes in HTLV-I-associated T-cell leukemia has not been investigated. Here we used whole genome next generation sequencing (NGS) of uncultured freshly isolated ATL samples and identified the presence of mutations in SUZ12, DNMT1, DNMT3A, DNMT3B, TET1, TET2, IDH1, IDH2, MLL, MLL2, MLL3 and MLL4. TET2 was the most frequently mutated gene, occurring in 32 % (10/31) of ATL samples analyzed. Interestingly, NGS revealed nonsense mutations accompanied by loss of heterozygosity (LOH) in TET2 and MLL3, which was further confirmed by cloning and direct sequencing of DNA from uncultured cells. Finally, direct sequencing of matched control and tumor samples revealed that TET2 mutation was present only in ATL tumor cells. Our results suggest that inactivation of MLL3 and TET2 may play an important role in the tumorigenesis process of HTLV-I-induced ATL.
    Full-text · Article · Dec 2016
    • "213, No. 8 JAK2 or c-MPL) or CALR (Klampfl et al., 2013; Nangalia et al., 2013). However, recent genome-wide sequencing studies revealed frequent co-occurring mutations in epigenetic regulators such as TET2, ASXL1, and EZH2 (Shih et al., 2012). Loss-of-function mutations in EZH2 have been identified in ∼10% of patients with PMF (Guglielmelli et al., 2011). "
    [Show abstract] [Hide abstract] ABSTRACT: EZH2 is a component of polycomb repressive complex 2 (PRC2) and functions as an H3K27 methyltransferase. Loss-of-function mutations in EZH2 are associated with poorer outcomes in patients with myeloproliferative neoplasms (MPNs), particularly those with primary myelofibrosis (MF [PMF]). To determine how EZH2 insufficiency is involved in the pathogenesis of PMF, we generated mice compound for an Ezh2 conditional deletion and activating mutation in JAK2 ( JAK2V617F ) present in patients with PMF. The deletion of Ezh2 in JAK2 V617F mice markedly promoted the development of MF, indicating a tumor suppressor function for EZH2 in PMF. The loss of Ezh2 in JAK2 V617F hematopoietic cells caused significant reductions in H3K27 trimethylation (H3K27me3) levels, resulting in an epigenetic switch to H3K27 acetylation (H3K27ac). These epigenetic switches were closely associated with the activation of PRC2 target genes including Hmga2 , an oncogene implicated in the pathogenesis of PMF. The treatment of JAK2 V617F /Ezh2 -null mice with a bromodomain inhibitor significantly attenuated H3K27ac levels at the promoter regions of PRC2 targets and down-regulated their expression, leading to the abrogation of MF-initiating cells. Therefore, an EZH2 insufficiency not only cooperated with active JAK2 to induce MF, but also conferred an oncogenic addiction to the H3K27ac modification in MF-initiating cells that was capable of being restored by bromodomain inhibition.
    Full-text · Article · Jul 2016
    • "It is possible that the effects of mutant IDH1 on DDR signaling do not allow the longterm survival and maintenance of IDH1-mutant HSCs in healthy individuals. Second, TET2 mutations are observed at higher Shih et al., 2012 ), whereas IDH1 mutations are observed at higher rates in AML (6%–16%) than in MDS (2%–4%) and MDS/MPN ($1%) (Im et al., 2014). Therefore, it may be the TET2-independent effects of IDH mutations, particularly their effects on DDR, that increase the probability of progressing to more advanced disease. "
    [Show abstract] [Hide abstract] ABSTRACT: Mutations in the isocitrate dehydrogenase-1 gene (IDH1) are common drivers of acute myeloid leukemia (AML) but their mechanism is not fully understood. It is thought that IDH1 mutants act by inhibiting TET2 to alter DNA methylation, but there are significant unexplained clinical differences between IDH1- and TET2-mutant diseases. We have discovered that mice expressing endogenous mutant IDH1 have reduced numbers of hematopoietic stem cells (HSCs), in contrast to Tet2 knockout (TET2-KO) mice. Mutant IDH1 downregulates the DNA damage (DD) sensor ATM by altering histone methylation, leading to impaired DNA repair, increased sensitivity to DD, and reduced HSC self-renewal, independent of TET2. ATM expression is also decreased in human IDH1-mutated AML. These findings may have implications for treatment of IDH-mutant leukemia.
    Full-text · Article · Jul 2016
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