@article{091aafb821694f7aa0502e3e199fddf9,
title = "Development of acute megakaryoblastic leukemia in Down syndrome is associated with sequential epigenetic changes",
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.",
author = "S{\'e}bastien Malinge and Tim Chlon and Dor{\'e}, {Louis C.} and Ketterling, {Rhett P.} and Tallman, {Martin S.} and Elisabeth Paietta and Gamis, {Alan S.} and Taub, {Jeffrey W.} and Chou, {Stella T.} and Weiss, {Mitchell J.} and Crispino, {John D.} and Figueroa, {Maria E.}",
note = "Funding Information: M.E.F. is supported in part by a Special Fellow Award from the Leukemia and Lymphoma Society. S.M. was supported by a Leukemia and Lymphoma Society Special Fellowship (no. 5110-10). This work was supported in part by grants from the National Cancer Institute (NCI) (CA101774) and the Samuel Waxman Cancer Research Foundation. J.W.T. is supported by an R01 grant from the NCI (CA120772). This work was partially funded by grant K08 HL093290 from the National Heart, Lung, and Blood Institute (NHLBI) (to S.T.C.) and The American Society of Hematology (to S.T.C.). This study was coordinated by the Eastern Cooperative Oncology Group (Robert L. Comis, Chair) and supported in part by Public Health Service Grants CA23318, CA66636, CA21115, CA17145, CA13650, CA15488, and CA14958 from the NCI, National Institutes of Health, and the Department of Health and Funding Information: The authors thank the Weill Cornell Medical Center Epigenetics Core Facility for performing the HELP microarrays and Jason Berman, Soheil Meshinchi, Todd Alonzo, and Sommer Castro and the Children's Oncology Group for their assistance with DS-AMKL specimens. This article's contents are solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. M.E.F. is supported in part by a Special Fellow Award from the Leukemia and Lymphoma Society. S.M. was supported by a Leukemia and Lymphoma Society Special Fellowship (no. 5110-10). This work was supported in part by grants from the National Cancer Institute (NCI) (CA101774) and the Samuel Waxman Cancer Research Foundation. J.W.T. is supported by an R01 grant from the NCI (CA120772). This work was partially funded by grant K08 HL093290 from the National Heart, Lung, and Blood Institute (NHLBI) (to S.T.C.) and The American Society of Hematology (to S.T.C.). This study was coordinated by the Eastern Cooperative Oncology Group (Robert L. Comis, Chair) and supported in part by Public Health Service Grants CA23318, CA66636, CA21115, CA17145, CA13650, CA15488, and CA14958 from the NCI, National Institutes of Health, and the Department of Health and Human Services. Research with DS-AMKL samples was supported by the Chair's Grant U10 CA98543 (to C.O.G.) from NCI. Publisher Copyright: {\textcopyright} 2013 by The American Society of Hematology.",
year = "2013",
doi = "10.1182/blood-2013-05-503011",
language = "English (US)",
volume = "122",
pages = "e33--e43",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "14",
}