<i>RASA4</i>undergoes DNA hypermethylation in resistant juvenile myelomonocytic leukemia

Poetsch, Anna R.; Lipka, Daniel B.; Witte, Tania; Claus, Rainer; Nöllke, Peter; Zucknick, Manuela; Olk-Batz, Christiane; Fluhr, Silvia; Dworzak, Michael; Moerloose, Barbara De; Starý, Jan; Zecca, Marco; Hasle, Henrik; Schmugge, Markus; Heuvel‐Eibrink, Marry M. van den; Locatelli, Franco; Niemeyer, Charlotte M.; Flotho, Christian; Plass, Christoph

doi:10.4161/epi.29941

Cited by 34 publications

(27 citation statements)

References 22 publications

(32 reference statements)

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“…[12][13][14][15][16][17][18][19][20][21][22] In an early study of ours, we identified disease-specific dysregulated genes and pathways using GeneChip analysis of bulk CD34 1 hematopoietic stem (HSCs) and progenitor cells (HSPCs) from patients with MDS with monosomy 7. 20 However, the absence of specific cell-membrane markers to separate cytogenetically normal and abnormal cells hindered further analysis of dysregulated molecular mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Single-cell RNA-seq reveals a distinct transcriptome signature of aneuploid hematopoietic cells

Zhao

Gao

et al. 2017

Blood

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Section: Introductionmentioning

confidence: 99%

Single-cell RNA-seq reveals a distinct transcriptome signature of aneuploid hematopoietic cells

Zhao

Gao

et al. 2017

Blood

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“…Evidence from the literature suggests that oncogenic RAS-signaling is able to modify epigenetic patterns [16][17][18] . Indeed, investigations of DNA methylation in JMML at the level of candidate gene promoters (AKAP12, BMP4, CALCA, CDKN2A, RARB, and RASA4) identified DNA hypermethylation to be associated with poor clinical outcome [19][20][21] . Still, to date, a comprehensive characterization of the DNA methylome in JMML is missing.…”

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confidence: 99%

Ras-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia

Lipka

Witte

Tóth

et al. 2017

Experimental Hematology

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Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of early childhood characterized by mutations activating RAS signaling. Established clinical and genetic markers fail to fully recapitulate the clinical and biological heterogeneity of this disease. Here we report DNA methylome analysis and mutation profiling of 167 JMML samples. We identify three JMML subgroups with unique molecular and clinical characteristics. The high methylation group (HM) is characterized by somatic PTPN11 mutations and poor clinical outcome. The low methylation group is enriched for somatic NRAS and CBL mutations, as well as for Noonan patients, and has a good prognosis. The intermediate methylation group (IM) shows enrichment for monosomy 7 and somatic KRAS mutations. Hypermethylation is associated with repressed chromatin, genes regulated by RAS signaling, frequent co-occurrence of RAS pathway mutations and upregulation of DNMT1 and DNMT3B, suggesting a link between activation of the DNA methylation machinery and mutational patterns in JMML.

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“…Alternatively, since recent literature described several differentially methylated loci in JMML, which all correlated with clinical outcome, it might be tempting to speculate that a global epigenetic re-patterning occurs during the onset of JMML pathogenesis. 7,8 Further studies will be needed to elucidate the exact molecular mechanisms leading to AKAP12a transcriptional repression and the impact of aberrant signaling in establishing aberrant methylation patterns within the AKAP12a promoter region.…”

Section: Akap12a Promoter Methylation Correlates With Clinical Prognomentioning

confidence: 99%

“…[3][4][5][6] Two recent studies linked aberrant DNA methylation patterns to an aggressive phenotype of JMML. 7,8 Using a candidate gene approach, a prognostic score based on four frequently hypermethylated genes (BMP4, CALCA, CDKN2B, and RARB) could be identified, which retained prognostic value independently of other clinical risk factors. 7 Several studies have shown that aberrant methylation patterns may be governed by deregulated signaling.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic silencing of AKAP12 in juvenile myelomonocytic leukemia

et al. 2016

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A-kinase anchor protein 12 (AKAP12) is a regulator of protein kinase A and protein kinase C signaling, acting downstream of RAS. Epigenetic silencing of AKAP12 has been demonstrated in different cancer entities and this has been linked to the process of tumorigenesis. Here, we used quantitative highresolution DNA methylation measurement by MassARRAY to investigate epigenetic regulation of all three AKAP12 promoters (i.e., a, b, and g) within a large cohort of juvenile myelomonocytic leukemia (JMML) patient samples. The AKAP12a promoter shows DNA hypermethylation in JMML samples, which is associated with decreased AKAP12a expression. Promoter methylation of AKAP12a correlates with older age at diagnosis, elevated levels of fetal hemoglobin and poor prognosis. In silico screening for transcription factor binding motifs around the sites of most pronounced methylation changes in the AKAP12a promoter revealed highly significant scores for GATA-2/-1 sequence motifs. Both transcription factors are known to be involved in the haematopoietic differentiation process. Methylation of a reporter construct containing this region resulted in strong suppression of AKAP12 promoter activity, suggesting that DNA methylation might be involved in the aberrant silencing of the AKAP12 promoter in JMML. Exposure to DNMT-and HDAC-inhibitors reactivates AKAP12a expression in vitro, which could potentially be a mechanism underlying clinical treatment responses upon demethylating therapy. Together, these data provide evidence for epigenetic silencing of AKAP12a in JMML and further emphasize the importance of dysregulated RAS signaling in JMML pathogenesis.

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RASA4undergoes DNA hypermethylation in resistant juvenile myelomonocytic leukemia

Cited by 34 publications

References 22 publications

Single-cell RNA-seq reveals a distinct transcriptome signature of aneuploid hematopoietic cells

Single-cell RNA-seq reveals a distinct transcriptome signature of aneuploid hematopoietic cells

Ras-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia

Epigenetic silencing of AKAP12 in juvenile myelomonocytic leukemia

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