Gene expression signatures of pediatric myelodysplastic syndromes are associated with risk of evolution into acute myeloid leukemia

Bresolin, Silvia; Trentin, Luca; Zecca, Marco; Giordan, Marco; Sainati, Laura; Locatelli, Franco; Basso, Giuseppe; Kronnie, Geertruy te

doi:10.1038/leu.2012.35

Cited by 6 publications

(6 citation statements)

References 15 publications

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“…This analysis showed that two distinct groups of MDS patients were generated although the mean age between the two groups was not statistically significantly different. One included four high-risk MDS patients (whose disease evolved into AML in a median interval between diagnosis and evolution of 225 days, range 59-714 days) and the other included low-risk MDS patients (whose disease had not evolved at the time of the study from 3-10 years after diagnosis) 26 ( Figure 2D). Therefore, differential expression of CREB target genes marks MDS, high-risk MDS (MDS that evolved) and AML, supporting the role of miR-34b and CREB in the process of myeloid transformation.…”

Section: Mir-34b Promoter Hypermethylation Occurs During Transformatimentioning

confidence: 99%

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MicroRNA-34b promoter hypermethylation induces CREB overexpression and contributes to myeloid transformation

et al. 2012

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ARTICLEShaematologica | 2013; 98(4) Molecular Aspects of LeukemiaMicroRNA-34b down-regulation in acute myeloid leukemia was previously shown to induce CREB overexpression, thereby causing leukemia proliferation in vitro and in vivo. The role of microRNA-34b and CREB in patients with myeloid malignancies has never been evaluated. We examined microRNA-34b expression and the methylation status of its promoter in cells from patients diagnosed with myeloid malignancies. We used gene expression profiling to identify signatures of myeloid transformation. We established that microRNA-34b has suppressor ability and that CREB has oncogenic potential in primary bone marrow cell cultures and in vivo. MicroRNA-34b was found to be up-regulated in pediatric patients with juvenile myelomonocytic leukemia (n=17) and myelodysplastic syndromes (n=28), but was down-regulated in acute myeloid leukemia patients at diagnosis (n=112). Our results showed that hypermethylation of the microRNA-34b promoter occurred in 66% of cases of acute myeloid leukemia explaining the low microRNA-34b levels and CREB overexpression, whereas preleukemic myelodysplastic syndromes and juvenile myelomonocytic leukemia were not associated with hypermethylation or CREB overexpression. In paired samples taken from the same patients when they had myelodysplastic syndrome and again during the subsequent acute myeloid leukemia, we confirmed microRNA-34b promoter hypermethylation at leukemia onset, with 103 CREB target genes differentially expressed between the two disease stages. This subset of CREB targets was confirmed to associate with high-risk myelodysplastic syndromes in a separate cohort of patients (n=20). Seventy-eight of these 103 CREB targets were also differentially expressed between healthy samples (n=11) and de novo acute myeloid leukemia (n=72). Further, low microRNA-34b and high CREB expression levels induced aberrant myelopoiesis through CREB-dependent pathways in vitro and in vivo. In conclusion, we suggest that microRNA-34b controls CREB expression and contributes to myeloid transformation from both healthy bone marrow and myelodysplastic syndromes. We identified a subset of CREB target genes that represents a novel transcriptional network that may control myeloid transformation.

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Section: Mir-34b Promoter Hypermethylation Occurs During Transformatimentioning

confidence: 99%

“…RNA quality was assessed on an Agilent2100 Bioanalyzer (Agilent Technologies). The GeneChip Human Genome U133 Plus 2.0 was used for the microarray experiments, as previously described [23][24][25][26] (Online Supplementary Design and Methods). …”

Section: Gene Expression Analysismentioning

confidence: 99%

MicroRNA-34b promoter hypermethylation induces CREB overexpression and contributes to myeloid transformation

et al. 2012

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“…Over the past 20 years, the protein complexes of S100A8 and S100A9 have emerged as very potent biomarkers of a wide range of inflammatory processes (Healy et al, 2006;Bresolin et al, 2012). Therefore, we speculate that S100A8 and S100A9 and the proteins with which they interact not only serve as useful markers of inflammation, but also play critical roles in the pathogenesis of inflammatory disorders.…”

Section: Discussionmentioning

confidence: 99%

Screening for feature genes associated with hereditary hemochromatosis and functional analysis with DNA microarrays

Wang¹,

Zhou²,

Li³

et al. 2013

Genet. Mol. Res.

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ABSTRACT. The aim of this study was to identify feature genes that are associated with hereditary hemochromatosis (HHC; iron overload) in cardiac and skeletal muscle of mice. First, the expression profile GSE9726 was downloaded from Gene Expression Omnibus database which included 12 samples. Then the differentially expressed genes (DEGs) were identified by R language. Furthermore, the KUPS software was used to identify relationships in interactions among common DEGs in the cardiac and skeletal muscles. We then used the EASE software to obtain enriched pathways in a gene interaction network. Finally, we used the plugins of the Cytoscape software, i.e., Mcode and Bingo, to conduct module analysis. By comparing diseased and normal tissue samples, 5 and 6 genes in the cardiac and skeletal muscles, respectively, were identified as DEGs. We observed that the S100a8 and S100a9 genes were common DEGs in both tissues examined. In addition, we constructed an interaction network with common DEGs and their interacting components, and identified S100a8 and S100a9 as being associated with immune responses. In view of the relationship between the early stage of myelodysplastic syndrome and the immune system, we hypothesize that 6241 ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 12 (4): 6240-6248 (2013) Identifying genes in hereditary hemochromatosis the expression of the S100a8 and S100a9 genes is a feature that can be used for diagnosis during the early stage of the myelodysplastic syndrome and that the 2 genes could be used as targets in treating this disease.

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“…These transcription factors are known regulators of hematopoietic stem cell proliferation [35][36][37][38] and are normally expressed at high levels in hematopoietic stem cells relative to more differentiated myelomonocytic cells [39][40][41][42]. Moreover, their activity has been implicated in myeloid leukemia [43][44][45][46], and expression of Gata2 and Hoxa9 has been demonstrated to be elevated in patients with myelodysplastic syndrome (MDS) [47][48][49][50]. qPCR revealed large increases in the transcript levels (8-to >200-fold) of all three genes in Rcor1-deficient Mac1 1 Gr1 lo cells relative to controls (Fig.…”

Section: Transcription Factors That Regulate Stem/progenitor Cell Promentioning

confidence: 99%

The Corepressor Rcor1 Is Essential for Normal Myeloerythroid Lineage Differentiation

et al. 2015

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Based on its physical interactions with histone-modifying enzymes, the transcriptional corepressor Rcor1 has been implicated in the epigenetic regulation blood cell development. Previously, we have demonstrated that Rcor1 is essential for the maturation of definitive erythroid cells and fetal survival. To determine the functional role of Rcor1 in steady-state hematopoiesis in the adult, we used a conditional knockout approach. Here, we show that the loss of Rcor1 expression results in the rapid onset of severe anemia due to a complete, cell autonomous block in the maturation of committed erythroid progenitors. By contrast, both the frequency of megakaryocyte progenitors and their capacity to produce platelets were normal. Although the frequency of common lymphoid progenitors and T cells was not altered, B cells were significantly reduced and showed increased apoptosis. However, Rcor1-deficient bone marrow sustained normal levels of B-cells following transplantation, indicating a non-cell autonomous requirement for Rcor1 in B-cell survival. Evaluation of the myelomonocytic lineage revealed an absence of mature neutrophils and a significant increase in the absolute number of monocytic cells. Rcor1-deficient monocytes were less apoptotic and showed~100-fold more colonyforming activity than their normal counterparts, but did not give rise to leukemia. Moreover, Rcor1 2/2 monocytes exhibited extensive, cytokine-dependent self-renewal and overexpressed genes associated with hematopoietic stem/progenitor cell expansion including Gata2, Meis1, and Hoxa9. Taken together, these data demonstrate that Rcor1 is essential for the normal differentiation of myeloerythroid progenitors and for appropriately regulating self-renewal activity in the monocyte lineage. STEM CELLS 2015;33:3304-3314 SIGNIFICANCE STATEMENTIn vitro interactions between histone modifying enzymes and the transcriptional co-repressor Rcor1 suggest it has an important role in the epigenetic regulation blood cell development. This study provides the first in vivo evidence that Rcor1 is essential for the normal production of mature red blood cells and neutrophils but not platelets. Rcor1-deficient monocytes are increased in number, have an enhanced capacity to self-renew, but remain cytokine dependent and do not give rise to leukemia. Rcor1 loss also leads to the aberrant expression of transcription factors that normally promote the replication of hematopoietic stem/progenitor cells. These findings demonstrate that Rcor1 is essential for red cell and neutrophil maturation while restricting the self-renewal potential of monocytes.

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Gene expression signatures of pediatric myelodysplastic syndromes are associated with risk of evolution into acute myeloid leukemia

Cited by 6 publications

References 15 publications

MicroRNA-34b promoter hypermethylation induces CREB overexpression and contributes to myeloid transformation

MicroRNA-34b promoter hypermethylation induces CREB overexpression and contributes to myeloid transformation

Screening for feature genes associated with hereditary hemochromatosis and functional analysis with DNA microarrays

The Corepressor Rcor1 Is Essential for Normal Myeloerythroid Lineage Differentiation

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