The leukemogenic AF4-MLL fusion protein causes P-TEFb kinase activation and altered epigenetic signatures

A Benedikt; S Baltruschat; B Scholz; A Bursen; T N Arrey; B Meyer; L Varagnolo; A M Müller; M Karas; T Dingermann; R Marschalek

doi:10.1038/leu.2010.249

The leukemogenic AF4-MLL fusion protein causes P-TEFb kinase activation and altered epigenetic signatures

Leukemia. 2011 Jan;25(1):135-44. doi: 10.1038/leu.2010.249. Epub 2010 Oct 29.

Authors

A Benedikt¹, S Baltruschat, B Scholz, A Bursen, T N Arrey, B Meyer, L Varagnolo, A M Müller, M Karas, T Dingermann, R Marschalek

Affiliation

¹ Institute of Pharmaceutical Biology/ZAFES, Goethe-University of Frankfurt, Biocenter, Frankfurt/Main, Germany.

PMID: 21030982
DOI: 10.1038/leu.2010.249

Abstract

Expression of the AF4-MLL fusion protein in murine hematopoietic progenitor/stem cells results in the development of proB acute lymphoblastic leukemia. In this study, we affinity purified the AF4-MLL and AF4 protein complexes to elucidate their function. We observed that the AF4 complex consists of 11 binding partners and exhibits positive transcription elongation factor b (P-TEFb)-mediated activation of promoter-arrested RNA polymerase (pol) II in conjunction with several chromatin-modifying activities. In contrast, the AF4-MLL complex consists of at least 16 constituents including P-TEFb kinase, H3K4(me3) and H3K79(me3) histone methyltransferases (HMT), a protein arginine N-methyltransferase and a histone acetyltransferase. These findings suggest that the AF4-MLL protein disturbs the fine-tuned activation cycle of promoter-arrested RNA Pol II and causes altered histone methylation signatures. Thus, we propose that these two processes are key to trigger cellular reprogramming that leads to the onset of acute leukemia.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Chromatography, Gel
DNA-Binding Proteins / isolation & purification
DNA-Binding Proteins / physiology*
Enzyme Activation
Epigenesis, Genetic*
Histone Methyltransferases
Histone-Lysine N-Methyltransferase / metabolism
Histones / metabolism
Humans
Leukemia / etiology*
Methylation
Myeloid-Lymphoid Leukemia Protein / isolation & purification
Myeloid-Lymphoid Leukemia Protein / physiology*
Nuclear Proteins / isolation & purification
Nuclear Proteins / physiology*
Oncogene Proteins, Fusion / isolation & purification
Oncogene Proteins, Fusion / physiology*
Phosphorylation
Positive Transcriptional Elongation Factor B / metabolism*
Transcriptional Elongation Factors

Substances

DNA-Binding Proteins
Histones
KMT2A protein, human
Nuclear Proteins
Oncogene Proteins, Fusion
Transcriptional Elongation Factors
Myeloid-Lymphoid Leukemia Protein
AFF1 protein, human
Histone Methyltransferases
Histone-Lysine N-Methyltransferase
Positive Transcriptional Elongation Factor B