Development of acute megakaryoblastic leukemia in Down syndrome is associated with sequential epigenetic changes.

Sébastien Malinge, Tim Chlon, Louis C. Doré, Rhett P. Ketterling, Martin S. Tallman, Elisabeth M. Paietta, Alan S. Gamis, Jeffrey W. Taub, Stella T. Chou, Mitchell J. Weiss, John D. Crispino, Maria E. Figueroa

Research output: Contribution to journalArticle

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Abstract

Acute megakaryoblastic leukemia (AMKL) is more frequently observed in Down syndrome (DS) patients, in whom it is often preceded by a transient myeloproliferative disorder (TMD). The development of DS-TMD and DS-AMKL requires not only the presence of the trisomy 21 but also that of GATA1 mutations. Despite extensive studies into the genetics of DS-AMKL, the importance of epigenetic deregulation in this disease has been unexplored. We performed DNA methylation profiling at different stages of development of DS-AMKL and analyzed the dynamics of the epigenetic program. Early genome-wide DNA methylation changes can be detected in trisomy 21 fetal liver mononuclear cells, prior to the acquisition of GATA1 mutations. These early changes are characterized by marked loss of DNA methylation at genes associated with developmental disorders, including those affecting the cardiovascular, neurological, and endocrine systems. This is followed by a second wave of changes detected in DS-TMD and DS-AMKL, characterized by gains of methylation. This new wave of hypermethylation targets a distinct set of genes involved in hematopoiesis and regulation of cell growth and proliferation. These findings indicate that the final epigenetic landscape of DS-AMKL is the result of sequential and opposing changes in DNA methylation occurring at specific times in the disease development.

Original languageEnglish (US)
JournalBlood
Volume122
Issue number14
DOIs
StatePublished - Oct 3 2013

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Leukemia, Megakaryoblastic, Acute
Down Syndrome
Epigenomics
Genes
DNA Methylation
Methylation
Deregulation
Cell proliferation
Cell growth
Liver
Myeloproliferative Disorders
Mutation
Endocrine System
DNA Fingerprinting
Hematopoiesis
Cardiovascular System
Cell Proliferation
Genome

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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Development of acute megakaryoblastic leukemia in Down syndrome is associated with sequential epigenetic changes. / Malinge, Sébastien; Chlon, Tim; Doré, Louis C.; Ketterling, Rhett P.; Tallman, Martin S.; Paietta, Elisabeth M.; Gamis, Alan S.; Taub, Jeffrey W.; Chou, Stella T.; Weiss, Mitchell J.; Crispino, John D.; Figueroa, Maria E.

In: Blood, Vol. 122, No. 14, 03.10.2013.

Research output: Contribution to journalArticle

Malinge, S, Chlon, T, Doré, LC, Ketterling, RP, Tallman, MS, Paietta, EM, Gamis, AS, Taub, JW, Chou, ST, Weiss, MJ, Crispino, JD & Figueroa, ME 2013, 'Development of acute megakaryoblastic leukemia in Down syndrome is associated with sequential epigenetic changes.', Blood, vol. 122, no. 14. https://doi.org/10.1182/blood-2013-05-503011
Malinge, Sébastien ; Chlon, Tim ; Doré, Louis C. ; Ketterling, Rhett P. ; Tallman, Martin S. ; Paietta, Elisabeth M. ; Gamis, Alan S. ; Taub, Jeffrey W. ; Chou, Stella T. ; Weiss, Mitchell J. ; Crispino, John D. ; Figueroa, Maria E. / Development of acute megakaryoblastic leukemia in Down syndrome is associated with sequential epigenetic changes. In: Blood. 2013 ; Vol. 122, No. 14.
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