RASA4 undergoes DNA hypermethylation in resistant juvenile myelomonocytic leukemia

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

doi:10.4161/epi.29941

RASA4 undergoes DNA hypermethylation in resistant juvenile myelomonocytic leukemia

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

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Abstract

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.

Original language	English
Pages (from-to)	1252-1260
Number of pages	9
Journal	Epigenetics
Volume	9
DOIs	https://doi.org/10.4161/epi.29941
Publication status	Published - 2014

Keywords

JMML
epigenetics,juvenile myelomonocytic leukemia
RASA4

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Poetsch, A. R., Lipka, D. B., Witte, T., Claus, R., Nöllke, P., Zucknick, M., Olk-Batz, C., Fluhr, S., Dworzak, M., De Moerloose, B., Starý, J., Zecca, M., Hasle, H., Schmugge, M., Van Den Heuvel-Eibrink, M. M., Locatelli, F., Niemeyer, C. M., Flotho, C., & Plass, C. (2014). RASA4 undergoes DNA hypermethylation in resistant juvenile myelomonocytic leukemia. Epigenetics, 9, 1252-1260. https://doi.org/10.4161/epi.29941

@article{606d17b517404a6ab1847f65e7b1ce08,

title = "RASA4 undergoes DNA hypermethylation in resistant juvenile myelomonocytic leukemia",

abstract = "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.",

keywords = "JMML, epigenetics,juvenile myelomonocytic leukemia, RASA4, JMML, epigenetics,juvenile myelomonocytic leukemia, RASA4",

author = "Poetsch, {Anna R.} and Lipka, {Daniel B.} and Tania Witte and Rainer Claus and Peter N{\"o}llke and Manuela Zucknick and Christiane Olk-Batz and Silvia Fluhr and Michael Dworzak and {De Moerloose}, Barbara and Jan Star{\'y} and Marco Zecca and Henrik Hasle and Markus Schmugge and {Van Den Heuvel-Eibrink}, {Marry M.} and Franco Locatelli and Niemeyer, {Charlotte M.} and Christian Flotho and Christoph Plass",

year = "2014",

doi = "10.4161/epi.29941",

language = "English",

volume = "9",

pages = "1252--1260",

journal = "Epigenetics",

issn = "1559-2294",

publisher = "Taylor and Francis Ltd.",

}

Poetsch, AR, Lipka, DB, Witte, T, Claus, R, Nöllke, P, Zucknick, M, Olk-Batz, C, Fluhr, S, Dworzak, M, De Moerloose, B, Starý, J, Zecca, M, Hasle, H, Schmugge, M, Van Den Heuvel-Eibrink, MM, Locatelli, F, Niemeyer, CM, Flotho, C & Plass, C 2014, 'RASA4 undergoes DNA hypermethylation in resistant juvenile myelomonocytic leukemia', Epigenetics, vol. 9, pp. 1252-1260. https://doi.org/10.4161/epi.29941

TY - JOUR

T1 - RASA4 undergoes DNA hypermethylation in resistant juvenile myelomonocytic leukemia

AU - Poetsch, Anna R.

AU - Lipka, Daniel B.

AU - Witte, Tania

AU - Claus, Rainer

AU - Nöllke, Peter

AU - Zucknick, Manuela

AU - Olk-Batz, Christiane

AU - Fluhr, Silvia

AU - Dworzak, Michael

AU - De Moerloose, Barbara

AU - Starý, Jan

AU - Zecca, Marco

AU - Hasle, Henrik

AU - Schmugge, Markus

AU - Van Den Heuvel-Eibrink, Marry M.

AU - Locatelli, Franco

AU - Niemeyer, Charlotte M.

AU - Flotho, Christian

AU - Plass, Christoph

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - JMML

KW - epigenetics,juvenile myelomonocytic leukemia

KW - RASA4

KW - JMML

KW - epigenetics,juvenile myelomonocytic leukemia

KW - RASA4

UR - http://hdl.handle.net/10807/243259

U2 - 10.4161/epi.29941

DO - 10.4161/epi.29941

M3 - Article

SN - 1559-2294

VL - 9

SP - 1252

EP - 1260

JO - Epigenetics

JF - Epigenetics

ER -

RASA4 undergoes DNA hypermethylation in resistant juvenile myelomonocytic leukemia

Abstract

Keywords

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