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

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.

Pubmed ID: 21030982

Authors

  • Benedikt A
  • Baltruschat S
  • Scholz B
  • Bursen A
  • Arrey TN
  • Meyer B
  • Varagnolo L
  • Müller AM
  • Karas M
  • Dingermann T
  • Marschalek R

Journal

Leukemia

Publication Data

January 12, 2011

Associated Grants

None

Mesh Terms

  • Chromatography, Gel
  • DNA-Binding Proteins
  • Enzyme Activation
  • Epigenesis, Genetic
  • Histone-Lysine N-Methyltransferase
  • Histones
  • Humans
  • Leukemia
  • Methylation
  • Myeloid-Lymphoid Leukemia Protein
  • Nuclear Proteins
  • Oncogene Proteins, Fusion
  • Phosphorylation
  • Positive Transcriptional Elongation Factor B