title: Impact of MLL5 expression on decitabine efficacy and DNA methylation in acute myeloid leukemia.
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 wild-type 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=0.026). In patients who received three or more courses decitabine, high MLL5 expression and wild-type DNMT3A independently predicted improved overall survival (median overall survival for high vs. low MLL5 expression 468 vs. 243 days; P=0.012). 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.
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem cell Transplantation, Hannover Medical School, Germany.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Yun
authors.affiliation: Department of Hematology, Oncology, and Tumor Immunology, Charité, Berlin, Germany.
authors.forename: Frederik
authors.initials: F
authors.lastname: Damm
authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Damian
authors.initials: D
authors.lastname: Yap
authors.affiliation: Institute of Experimental Hematology, Hannover Medical School, Germany.
authors.forename: Adrian
authors.initials: A
authors.lastname: Schwarzer
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem cell Transplantation, Hannover Medical School, Germany.
authors.forename: Anuhar
authors.initials: A
authors.lastname: Chaturvedi
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem cell Transplantation, Hannover Medical School, Germany.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Jyotsana
authors.affiliation: Division of Hematology and Oncology, University of Freiburg Medical Center, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Lübbert
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Bullinger
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Germany.
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
authors.affiliation: Department of Cell Biology and Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Geffers
authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Samuel
authors.initials: S
authors.lastname: Aparicio
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: R Keith
authors.initials: RK
authors.lastname: Humphries
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem cell Transplantation, Hannover Medical School, Germany.
authors.forename: Arnold
authors.initials: A
authors.lastname: Ganser
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem cell Transplantation, Hannover Medical School, Germany heuser.michael@mh-hannover.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Heuser
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D000090205:DNA Methyltransferase 3A; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D000077209:Decitabine; D004334:Drug Administration Schedule; D005260:Female; D015870:Gene Expression; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D016019:Survival Analysis
chemical_list: D000964:Antimetabolites, Antineoplastic; D004268:DNA-Binding Proteins; C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; C460660:KMT2E protein, human; D012333:RNA, Messenger; D000077209:Decitabine; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D001374:Azacitidine