Interplay of RUNX1/MTG8 and DNA methyltransferase 1 in acute myeloid leukemia.
The translocation t(8;21)(q22;q22) in acute myeloid leukemia (AML) results in the expression of the fusion protein RUNX1/MTG8, which in turn recruits histone deacetylases (HDAC) to silence RUNX1 target genes [e.g., interleukin-3 (IL-3)]. We previously reported that expression of the RUNX1/MTG8 target gene IL-3 is synergistically restored by the combination of inhibitors of HDACs (i.e., depsipeptide) and DNA methyltransferases (DNMT; i.e., decitabine) in RUNX1/MTG8-positive Kasumi-1 cells. Thus, we hypothesized that DNMT1 is also part of the transcriptional repressor complex recruited by RUNX1/MTG8. By a chromatin immunoprecipitation assay, we identified a RUNX1/MTG8-DNMT1 complex on the IL-3 promoter in Kasumi-1 cells and in primary RUNX1/MTG8-positive AML blasts. The physical association of RUNX1/MTG8 with DNMT1 was shown by coimmunoprecipitation experiments. Furthermore, RUNX1/MTG8 and DNMT1 were concurrently released from the IL-3 promoter by exposure to depsipeptide or stabilized on the promoter by decitabine treatment. Finally, we proved that RUNX1/MTG8 and DNMT1 were functionally interrelated by showing an enhanced repression of IL-3 after coexpression in 293T cells. These results suggest a novel mechanism for gene silencing mediated by RUNX1/MTG8 and support the combination of HDAC and DNMT inhibitors as a novel therapeutic approach for t(8;21) AML.
Liu
Shujun
S
Divisions of Hematology-Oncology, Department of Internal Medicine and the Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA.
Shen
Tiansheng
T
Huynh
Lenguyen
L
Klisovic
Marko I
MI
Rush
Laura J
LJ
Ford
Jamie L
JL
Yu
Jianhua
J
Becknell
Brian
B
Li
Yu
Y
Liu
Chunhui
C
Vukosavljevic
Tamara
T
Whitman
Susan P
SP
Chang
Kun-Sang
KS
Byrd
John C
JC
Perrotti
Danilo
D
Plass
Christoph
C
Marcucci
Guido
G
D000208:Acute Disease; D002460:Cell Line; D045744:Cell Line, Tumor; D050676:Core Binding Factor Alpha 2 Subunit; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D020868:Gene Silencing; D006801:Humans; D007377:Interleukin-3 / Q000235:genetics; D007951:Leukemia, Myeloid / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology; D014162:Transfection
D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D007377:Interleukin-3; D011518:Proto-Oncogene Proteins; D000075142:RUNX1 Translocation Partner 1 Protein; C493728:RUNX1 protein, human; C082222:RUNX1T1 protein, human; D014157:Transcription Factors; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human