Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms. Blood

Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, OH 44195, USA.
Blood (Impact Factor: 10.45). 05/2009; 113(25):6403-10. DOI: 10.1182/blood-2009-02-205690
Source: PubMed


Chromosomal abnormalities are frequent in myeloid malignancies, but in most cases of myelodysplasia (MDS) and myeloproliferative neoplasms (MPN), underlying pathogenic molecular lesions are unknown. We identified recurrent areas of somatic copy number-neutral loss of heterozygosity (LOH) and deletions of chromosome 4q24 in a large cohort of patients with myeloid malignancies including MDS and related mixed MDS/MPN syndromes using single nucleotide polymorphism arrays. We then investigated genes in the commonly affected area for mutations. When we sequenced TET2, we found homozygous and hemizygous mutations. Heterozygous and compound heterozygous mutations were found in patients with similar clinical phenotypes without LOH4q24. Clinical analysis showed most TET2 mutations were present in patients with MDS/MPN (58%), including CMML (6/17) or sAML (32%) evolved from MDS/MPN and typical MDS (10%), suggesting they may play a ubiquitous role in malignant evolution. TET2 mutations affected conserved domains and the N terminus. TET2 is widely expressed in hematopoietic cells but its function is unknown, and it lacks homology to other known genes. The frequency of mutations in this candidate myeloid regulatory gene suggests an important role in the pathogenesis of poor prognosis MDS/MPN and sAML and may act as a disease gene marker for these often cytogenetically normal disorders.

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    • "TET2 mutation is enriched amongst cases of myeloid malignancy occurring in approximately 12% of acute myeloid leukemia (AML) cases and up to 58% of mixed myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS) [12–14]. Therefore, it is likely that TET2 plays an important role in regulation of hematopoietic differentiation and may even serve as a prognostic tool in myeloid malignancies. "
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    ABSTRACT: TET2 is a methylcytosine dioxygenase that is frequently mutated in myeloid malignancies, notably myelodysplasia and acute myeloid leukemia. TET2 catalyses the conversion of 5'-methylcytosine to 5'-hydroxymethylcytosine within DNA and has been implicated in the process of genomic demethylation. However, the mechanism by which TET2 loss of function results in hematopoietic dysplasia and leukemogenesis is poorly understood. Here, we show that TET2 is expressed in undifferentiated embryonic stem cells and that its knockdown results in reduction of 5'-hydroxymethylcytosine in genomic DNA. We also present DNA methylation data from bone marrow samples obtained from patients with TET2-mutated myelodysplasia. Based on these findings, we sought to identify the role of TET2 in regulating pluripotency and differentiation. We show that overexpression of TET2 in a stably integrated transgene leads to increased alkaline phosphatase expression in differentiating ES cells and impaired differentiation in methylcellulose culture. We speculate that this effect is due to TET2-mediated expression of stem cell genes in ES cells via hydroxylation of 5'-methylcytosines at key promoter sequences within genomic DNA. This leads to relative hypomethylation of gene promoters as 5'-hydroxymethylcytosine is not a substrate for DNMT1-mediated maintenance methylation. We sought to test this hypothesis by cotransfecting the TET2 gene with methylated reporter genes. The results of these experiments are presented.
    08/2014; 2014:986571. DOI:10.1155/2014/986571
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    • "These mutated genes are located on chromosomes 20, 7, 21, and 4, respectively. Recent studies have shown that TET2 mutations are present in up to 30% of MDS/MPN cases, with mutations in ASXL1, EZH2, and RUNX1 also commonly reported [43]. The finding of mutations in all four of these myeloid regulatory genes suggests that they play a critical role in the pathogenesis of this case and demonstrate that mutation analysis is useful in cytogenetically normal myeloid disorders [43]. "
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    ABSTRACT: Advances in genome-wide molecular cytogenetics allow identification of novel submicroscopic DNA copy number alterations (aCNAs) and copy-neutral loss of heterozygosity (cnLOH) resulting in homozygosity for known gene mutations in myeloid neoplasms. We describe the use of an oligo-SNP array for genomic profiling of aCNA and cnLOH, together with sequence analysis of recurrently mutated genes, in a patient with myelodysplastic syndrome (MDS) presenting with normal karyotype and FISH results. Oligo-SNP array analysis revealed a hemizygous deletion of 896 kb at chromosome 5q31.2, representing the smallest 5q deletion reported to date. The deletion involved multiple genes, including two tumor suppressor candidate genes (CTNNA1 and HSPA9) that are associated with MDS/AML. The SNP-array study also detected 3 segments of somatic cnLOH: one involved the entire long arm of chromosome 4; the second involved the distal half of the long arm of chromosome 7, and the third encompassed the entire chromosome 22 (UPD 22). Sequence analysis revealed mutations in TET2 (4q), EZH2 (7q), ASXL1 (20q11.21), and RUNX1 (21q22.3). Coincidently, TET2 and EZH2 were located at segments of cnLOH resulting in their homozygosity. Loss of heterozygosity affecting these two chromosomes and mutations in TET2 and EZH2 are indicative of a myelodysplastic syndrome with a poor prognosis. Deletion of the tumor suppressor genes CTNNA1 and HSPA9 is also likely to contribute to a poor prognosis. Furthermore, the original cnLOHs in multiple chromosomes and additional cnLOH 14q in the follow-up study suggest genetic evolution of the disease and poor prognosis. This study attests to the fact that some patients with a myelodysplastic syndrome who exhibit a normal karyotype may have underlying genetic abnormalities detectable by chromosomal microarray and/or targeted mutation analyses.
    Molecular Cytogenetics 05/2014; 7(1):35. DOI:10.1186/1755-8166-7-35 · 2.14 Impact Factor
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    • "Further, Nibourel and colleagues reported no association with OS or DFS in their cohort of de novo AML patients, though the prevalence of TET2 mutations in patients who failed to achieve complete remission (CR) trended higher (27% vs. 17%) (Nibourel et al., 2010). Despite questionable association to patient outcomes, TET2 mutations are linked with other clinical features, including monocytosis, leukocytosis, and advanced age at diagnosis (Jankowska et al., 2009; Smith et al., 2010; Tefferi et al., 2009a; Tefferi et al., 2009c). Although TET2 mutations show little association to known myeloid leukemogenic drivers—FLT3-ITD, RUNX1, CEBPA—they do associate with NPM1 and ASXL1 mutations and infrequently co-occur with IDH1 or IDH2 mutations (Chou et al., 2011a; Weissmann et al., 2012). "
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    ABSTRACT: Epigenetic alterations are associated with all aspects of cancer, from tumor initiation to cancer progression and metastasis. It is now well understood that both losses and gains of DNA methylation as well as altered chromatin organization contribute significantly to cancer-associated phenotypes. More recently, new sequencing technologies have allowed the identification of driver mutations in epigenetic regulators, providing a mechanistic link between the cancer epigenome and genetic alterations. Oncogenic activating mutations are now known to occur in a number of epigenetic modifiers (i.e. IDH1/2, EZH2, DNMT3A), pinpointing epigenetic pathways that are involved in tumorigenesis. Similarly, investigations into the role of inactivating mutations in chromatin modifiers (i.e. KDM6A, CREBBP/EP300, SMARCB1) implicate many of these genes as tumor suppressors. Intriguingly, a number of neoplasms are defined by a plethora of mutations in epigenetic regulators, including renal, bladder, and adenoid cystic carcinomas. Particularly striking is the discovery of frequent histone H3.3 mutations in pediatric glioma, a particularly aggressive neoplasm that has long remained poorly understood. Cancer epigenetics is a relatively new, promising frontier with much potential for improving cancer outcomes. Already, therapies such as 5-azacytidine and decitabine have proven that targeting epigenetic alterations in cancer can lead to tangible benefits. Understanding how genetic alterations give rise to the cancer epigenome will offer new possibilities for developing better prognostic and therapeutic strategies.
    Protein & Cell 03/2014; 5(4). DOI:10.1007/s13238-014-0031-6 · 3.25 Impact Factor
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