Mutations in epigenetic regulators in myelodysplastic syndromes

Nikoloski, Gorica; Reijden, Bert A. van der; Jansen, Joop H.

doi:10.1007/s12185-011-0996-3

Cited by 27 publications

(22 citation statements)

References 68 publications

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“…Mutations in ASXL1 (exon 12), CBL (exons 8, 9), DNMT3A (exons [15][16][17][18][19][20][21][22][23], EZH2 (all exons), FLT3 (exons 14,15,20), IDH1/2 (exons 4), JAK2 (exon 14), NF1 (exons 1-50), N/KRAS (exons 1, 2), PTPN11 (exons 3, 11) ), RUNX1 (exons 1-8), SF3B1 (exons 12-16), SUZ12 (exons 14-16), SRSF2 (exon 2), TET2 (exons 3-11), U2AF35/U2AF1 (exons 2, 6), and ZRSR2 (exons 1-11) were analyzed using BM DNA as previously described.…”

Section: Sequencing Of 18 Candidate Genesmentioning

confidence: 99%

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Molecular similarity between myelodysplastic form of chronic myelomonocytic leukemia and refractory anemia with ring sideroblasts

Gelsi‐Boyer¹,

Cervera²,

Bertucci³

et al. 2012

Haematologica

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ABSTRACT(aCGH) and sequencing of candidate genes. 7,8 According to the French-American-British (FAB) 6 and WHO 3 classifications, the CMML series was made up of 31 MP and 22 MD cases (Online Supplementary Table S1) and the MDS panel 8 refractory anemia (RA) with ring sideroblasts (RARS), 13 RA with excess of blasts type 1 (RAEB1) and 11 RAEB type 2 (RAEB2). CMML and MDS cases selected for gene expression profiling were collected at the time of diagnosis or in therapeutic abstention; none had been treated. All patients signed an informed consent for research and the study was approved by our institutional review board ("Comité d'Orientation Scientifique" of the Institut PaoliCalmettes). CD34 enrichmentSamples were enriched in CD34-positive (CD34 + ) cells for 12 CMML and 32 MDS cases. Leukocytes were obtained after bone marrow red cell lysis and washing with PBS, and labeled with magnetic bead-conjugated anti-CD34 monoclonal antibody (AC34 MicroBead; Miltenyi Biotec, Auburn, CA, USA). CD34 + hematopoietic stem cell populations were then purified through a miniMACS magnetic cell separation column (Miltenyi Biotec). RNA/DNA extractionRNAs and DNAs were extracted from whole BM CMML samples. After BM aspiration, a red cell lysis was carried out, followed by rinses with PBS. Leukocytes were processed immediately or cryopreserved at -80°C at the sample bank of the Institute and processed later. DNA and RNA were extracted using Nucleobond RNA/DNA kit from Macherey-Nagel (Düren, Germany) as recommended by the supplier. RNA from CD34 + cells were similarly extracted using Nucleobond RNA/DNA kit from Macherey-Nagel. Sequencing of 18 candidate genesMutations in ASXL1 (exon 12), CBL (exons 8, 9), DNMT3A (exons 15-23), EZH2 (all exons), FLT3 (exons 14, 15, 20), IDH1/2 (exons 4), JAK2 (exon 14), NF1 (exons 1-50), N/KRAS (exons 1, 2), PTPN11 (exons 3, 11) ), RUNX1 (exons 1-8), SF3B1 (exons 12-16), SUZ12 (exons 14-16), SRSF2 (exon 2), TET2 (exons 3-11), U2AF35/U2AF1 (exons 2, 6), and ZRSR2 (exons 1-11) were analyzed using BM DNA as previously described. 7-11 Gene expression profilingGene expression profiles of 39 CMML (out of the 53) and 32 MDS (all from CD34 + cells) mRNAs were established. Among the 39 CMML cases, 37 were studied as BM (10 of these were also studied as CD34 + ) and 2 as CD34 + RNAs. In other words, 10 CMML samples were studied as both CD34 + and whole BM RNAs, and 2 as CD34 + only (12 CD34 + in total). RNA quality and purity were assessed with Agilent Bioanalyzer 2100 (Agilent Technologies, Palo Alto, CA, USA). Preparation of cRNA, hybridizations onto Affymetrix U133 Plus 2.0 human oligonucleotide microarrays, washes and detection were carried out as recommended by the supplier and as previously described. Data were analyzed by the Robust Multichip Average (RMA) method in R using Bioconductor and associated package, as previously described.12 Before analysis, a first filtering process removed from the data set the probe sets with low and poorly measured expression as defined by an expression value inferior to ...

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Section: Sequencing Of 18 Candidate Genesmentioning

confidence: 99%

“…Could this similarity be the result of gene mutations common and specific to the two diseases? We 7,8,18 and others [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] have previously studied several leukemogenic genes in CMML and RARS. However, several of those (e.g.…”

mentioning

confidence: 99%

Molecular similarity between myelodysplastic form of chronic myelomonocytic leukemia and refractory anemia with ring sideroblasts

Gelsi‐Boyer¹,

Cervera²,

Bertucci³

et al. 2012

Haematologica

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“…As further support for this, ASXL1 mutations are usually heterozygous, leaving 1 allele intact. Therefore, we hypothesized that the C-terminal truncated form of ASXL1 might function as a dominant-negative mutant that suppresses the ASXL1-WT function or alternatively as a gain-of-function mutant (14,15). These possible effects of ASXL1 mutations have not been studied and are critical to delineate given the clinical importance of ASXL1 mutations.…”

Section: Introductionmentioning

confidence: 99%

Myelodysplastic syndromes are induced by histone methylationâ€“altering ASXL1 mutations

et al. 2013

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Recurrent mutations in the gene encoding additional sex combs-like 1 (ASXL1) are found in various hematologic malignancies and associated with poor prognosis. In particular, ASXL1 mutations are common in patients with hematologic malignancies associated with myelodysplasia, including myelodysplastic syndromes (MDSs), and chronic myelomonocytic leukemia. Although loss-of-function ASXL1 mutations promote myeloid transformation, a large subset of ASXL1 mutations is thought to result in stable truncation of ASXL1. Here we demonstrate that C-terminal-truncating Asxl1 mutations (ASXL1-MTs) inhibited myeloid differentiation and induced MDS-like disease in mice. ASXL1-MT mice displayed features of human-associated MDS, including multilineage myelodysplasia, pancytopenia, and occasional progression to overt leukemia. ASXL1-MT resulted in derepression of homeobox A9 (Hoxa9) and microRNA-125a (miR-125a) expression through inhibition of polycomb repressive complex 2-mediated (PRC2-mediated) methylation of histone H3K27. miR-125a reduced expression of C-type lectin domain family 5, member a (Clec5a), which is involved in myeloid differentiation. In addition, HOXA9 expression was high in MDS patients with ASXL1-MT, while CLEC5A expression was generally low. Thus, ASXL1-MT-induced MDS-like disease in mice is associated with derepression of Hoxa9 and miR-125a and with Clec5a dysregulation. Our data provide evidence for an axis of MDS pathogenesis that implicates both ASXL1 mutations and miR-125a as therapeutic targets in MDS.

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“…TET2 is the most frequent gene abnormality in MDS (Kosmider et al 2009;Langemeijer et al 2009), and DNMT3A mutation is a very early genetic event in MDS . These mutations in epigenetic modifiers indicate that epigenetic changes contribute to MDS pathogenesis (Graubert and Walter 2011;Nikoloski et al 2012).…”

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confidence: 99%

Age-related epigenetic drift in the pathogenesis of MDS and AML

et al. 2014

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The myelodysplastic syndrome (MDS) is a clonal hematologic disorder that frequently evolves to acute myeloid leukemia (AML). Its pathogenesis remains unclear, but mutations in epigenetic modifiers are common and the disease often responds to DNA methylation inhibitors. We analyzed DNA methylation in the bone marrow and spleen in two mouse models of MDS/AML, the NUP98-HOXD13 (NHD13) mouse and the RUNX1 mutant mouse model. Methylation array analysis showed an average of 512/3445 (14.9%) genes hypermethylated in NHD13 MDS, and 331 (9.6%) genes hypermethylated in RUNX1 MDS. Thirty-two percent of genes in common between the two models (2/3 NHD13 mice and 2/3 RUNX1 mice) were also hypermethylated in at least two of 19 human MDS samples. Detailed analysis of 41 genes in mice showed progressive drift in DNA methylation from young to old normal bone marrow and spleen; to MDS, where we detected accelerated agerelated methylation; and finally to AML, which markedly extends DNA methylation abnormalities. Most of these genes showed similar patterns in human MDS and AML. Repeat element hypomethylation was rare in MDS but marked the transition to AML in some cases. Our data show consistency in patterns of aberrant DNA methylation in human and mouse MDS and suggest that epigenetically, MDS displays an accelerated aging phenotype.

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Mutations in epigenetic regulators in myelodysplastic syndromes

Cited by 27 publications

References 68 publications

Molecular similarity between myelodysplastic form of chronic myelomonocytic leukemia and refractory anemia with ring sideroblasts

Molecular similarity between myelodysplastic form of chronic myelomonocytic leukemia and refractory anemia with ring sideroblasts

Myelodysplastic syndromes are induced by histone methylationâ€“altering ASXL1 mutations

Age-related epigenetic drift in the pathogenesis of MDS and AML

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