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RASA4 undergoes DNA hypermethylation in resistant juvenile myelomonocytic leukemia

AR. Poetsch, DB. Lipka, T. Witte, R. Claus, P. Nöllke, M. Zucknick, C. Olk-Batz, S. Fluhr, M. Dworzak, B. De Moerloose, J. Starý, M. Zecca, H. Hasle, M. Schmugge, MM. van den Heuvel-Eibrink, F. Locatelli, CM. Niemeyer, C. Flotho, C. Plass,

. 2014 ; 9 (9) : 1252-60.

Language English Country United States

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc15023108

Aberrant DNA methylation at specific genetic loci is a key molecular feature of juvenile myelomonocytic leukemia (JMML) with poor prognosis. Using quantitative high-resolution mass spectrometry, we identified RASA4 isoform 2, which maps to chromosome 7 and encodes a member of the GAP1 family of GTPase-activating proteins for small G proteins, as a recurrent target of isoform-specific DNA hypermethylation in JMML (51% of 125 patients analyzed). RASA4 isoform 2 promoter methylation correlated with clinical parameters predicting poor prognosis (older age, elevated fetal hemoglobin), with higher risk of relapse after hematopoietic stem cell transplantation, and with PTPN11 mutation. The level of isoform 2 methylation increased in relapsed cases after transplantation. Interestingly, most JMML cases with monosomy 7 exhibited hypermethylation on the remaining RASA4 allele. The results corroborate the significance of epigenetic modifications in the phenotype of aggressive JMML.

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$a Aberrant DNA methylation at specific genetic loci is a key molecular feature of juvenile myelomonocytic leukemia (JMML) with poor prognosis. Using quantitative high-resolution mass spectrometry, we identified RASA4 isoform 2, which maps to chromosome 7 and encodes a member of the GAP1 family of GTPase-activating proteins for small G proteins, as a recurrent target of isoform-specific DNA hypermethylation in JMML (51% of 125 patients analyzed). RASA4 isoform 2 promoter methylation correlated with clinical parameters predicting poor prognosis (older age, elevated fetal hemoglobin), with higher risk of relapse after hematopoietic stem cell transplantation, and with PTPN11 mutation. The level of isoform 2 methylation increased in relapsed cases after transplantation. Interestingly, most JMML cases with monosomy 7 exhibited hypermethylation on the remaining RASA4 allele. The results corroborate the significance of epigenetic modifications in the phenotype of aggressive JMML.
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$a Lipka, Daniel B $u Division of Epigenomics and Cancer Risk Factors (C010); German Cancer Research Center; Heidelberg, Germany.
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$a Witte, Tania $u Division of Epigenomics and Cancer Risk Factors (C010); German Cancer Research Center; Heidelberg, Germany.
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$a Claus, Rainer $u Division of Epigenomics and Cancer Risk Factors (C010); German Cancer Research Center; Heidelberg, Germany.
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$a Nöllke, Peter $u Division of Pediatric Hematology-Oncology; University Medical Center; Freiburg, Germany.
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$a Zucknick, Manuela $u Division of Biostatistics; German Cancer Research Center; Heidelberg, Germany.
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$a Olk-Batz, Christiane $u Division of Pediatric Hematology-Oncology; University Medical Center; Freiburg, Germany.
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$a Fluhr, Silvia $u Division of Pediatric Hematology-Oncology; University Medical Center; Freiburg, Germany.
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$a Dworzak, Michael $u St. Anna Children's Hospital and Children's Cancer Research Institute; Department of Pediatrics; Medical University of Vienna; Vienna, Austria.
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$a De Moerloose, Barbara $u Dept. of Pediatric Hematology-Oncology; Ghent University Hospital; Ghent, Belgium.
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$a Starý, Jan $u Dept. of Pediatric Hematology and Oncology; 2nd Faculty of Medicine; Charles University and University Hospital Motol, Praha; Czech Pediatric Hematology Working Group (CPH); Prague, Czech Republic.
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$a Zecca, Marco $u Pediatric Hematology-Oncology; Fondazione IRCCS;Policlinico San Matteo; Pavia, Italy.
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$a Hasle, Henrik $u Department of Pediatrics; Aarhus University Hospital Skejby; Aarhus, Denmark.
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$a Schmugge, Markus $u Division of Hematology; University Children's Hospital; Zurich, Switzerland.
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$a van den Heuvel-Eibrink, Marry M $u Department of Pediatric Oncology-Hematology; Erasmus Medical Center; Rotterdam, The Netherlands; Dutch Children's Oncology Group; The Hague, Netherlands.
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$a Locatelli, Franco $u Department of Pediatric Hematology-Oncology; IRCCS Ospedale Bambino Gesu; Rome, Italy; University of Pavia; Pavia, Italy.
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$a Niemeyer, Charlotte M $u The German Cancer Consortium; Heidelberg, Germany; Division of Pediatric Hematology-Oncology; University Medical Center; Freiburg, Germany.
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$a Flotho, Christian $u The German Cancer Consortium; Heidelberg, Germany; Division of Pediatric Hematology-Oncology; University Medical Center; Freiburg, Germany.
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$a Plass, Christoph $u Division of Epigenomics and Cancer Risk Factors (C010); German Cancer Research Center; Heidelberg, Germany; The German Cancer Consortium; Heidelberg, Germany.
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