Impact of MLL5 expression on decitabine efficacy and DNA methylation in acute myeloid leukemia.

2.50
Hdl Handle:
http://hdl.handle.net/10033/321973
Title:
Impact of MLL5 expression on decitabine efficacy and DNA methylation in acute myeloid leukemia.
Authors:
Yun, Haiyang; Damm, Frederik; Yap, Damian; Schwarzer, Adrian; Chaturvedi, Anuhar; Jyotsana, Nidhi; Lübbert, Michael; Bullinger, Lars; Döhner, Konstanze; Geffers, Robert ( 0000-0003-4409-016X ) ; Aparicio, Samuel; Humphries, R Keith; Ganser, Arnold; Heuser, Michael
Abstract:
Hypomethylating agents are widely used in patients with myelodysplastic syndromes and unfit patients with acute myeloid leukemia. However, it is not well understood why only some patients respond to hypomethylating agents. We found previously that the effect of decitabine on hematopoietic stem cell viability differed between Mll5 wildtype and null cells. We therefore investigated the role of MLL5 expression levels on outcome of acute myeloid leukemia patients who were treated with decitabine. MLL5 above the median expression level predicted longer overall survival independent of DNMT3A mutation status in bivariate analysis (median overall survival for high vs. low MLL5 expression, 292 vs. 167 days, P=.026). In patients who received 3 or more courses decitabine, high MLL5 expression and wildtype DNMT3A independently predicted improved overall survival (median overall survival for high vs. low MLL5 expression, 468 vs. 243 days, P=.012). In transformed murine cells, loss of Mll5 was associated with resistance to low-dose decitabine, less global DNA methylation in promoter regions, and reduced DNA demethylation upon decitabine treatment. Together, these data support our clinical observation of improved outcome in decitabine treated patients who express MLL5 at high levels, and suggest a mechanistic role of MLL5 in the regulation of DNA methylation.
Citation:
Impact of MLL5 expression on decitabine efficacy and DNA methylation in acute myeloid leukemia. 2014: Haematologica
Journal:
Haematologica
Issue Date:
3-Jun-2014
URI:
http://hdl.handle.net/10033/321973
DOI:
10.3324/haematol.2013.101386
PubMed ID:
24895338
Type:
Article
ISSN:
1592-8721
Appears in Collections:
publications of the research group genomeanalytics (GMAK)

Full metadata record

DC FieldValue Language
dc.contributor.authorYun, Haiyangen
dc.contributor.authorDamm, Frederiken
dc.contributor.authorYap, Damianen
dc.contributor.authorSchwarzer, Adrianen
dc.contributor.authorChaturvedi, Anuharen
dc.contributor.authorJyotsana, Nidhien
dc.contributor.authorLübbert, Michaelen
dc.contributor.authorBullinger, Larsen
dc.contributor.authorDöhner, Konstanzeen
dc.contributor.authorGeffers, Roberten
dc.contributor.authorAparicio, Samuelen
dc.contributor.authorHumphries, R Keithen
dc.contributor.authorGanser, Arnolden
dc.contributor.authorHeuser, Michaelen
dc.date.accessioned2014-06-19T13:59:17Zen
dc.date.available2014-06-19T13:59:17Zen
dc.date.issued2014-06-03en
dc.identifier.citationImpact of MLL5 expression on decitabine efficacy and DNA methylation in acute myeloid leukemia. 2014: Haematologicaen
dc.identifier.issn1592-8721en
dc.identifier.pmid24895338en
dc.identifier.doi10.3324/haematol.2013.101386en
dc.identifier.urihttp://hdl.handle.net/10033/321973en
dc.description.abstractHypomethylating agents are widely used in patients with myelodysplastic syndromes and unfit patients with acute myeloid leukemia. However, it is not well understood why only some patients respond to hypomethylating agents. We found previously that the effect of decitabine on hematopoietic stem cell viability differed between Mll5 wildtype and null cells. We therefore investigated the role of MLL5 expression levels on outcome of acute myeloid leukemia patients who were treated with decitabine. MLL5 above the median expression level predicted longer overall survival independent of DNMT3A mutation status in bivariate analysis (median overall survival for high vs. low MLL5 expression, 292 vs. 167 days, P=.026). In patients who received 3 or more courses decitabine, high MLL5 expression and wildtype DNMT3A independently predicted improved overall survival (median overall survival for high vs. low MLL5 expression, 468 vs. 243 days, P=.012). In transformed murine cells, loss of Mll5 was associated with resistance to low-dose decitabine, less global DNA methylation in promoter regions, and reduced DNA demethylation upon decitabine treatment. Together, these data support our clinical observation of improved outcome in decitabine treated patients who express MLL5 at high levels, and suggest a mechanistic role of MLL5 in the regulation of DNA methylation.en
dc.languageENGen
dc.rightsArchived with thanks to Haematologicaen
dc.titleImpact of MLL5 expression on decitabine efficacy and DNA methylation in acute myeloid leukemia.en
dc.typeArticleen
dc.identifier.journalHaematologicaen

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