AFF4, a Component of the ELL/P-TEFb Elongation Complex and a Shared Subunit of MLL Chimeras, Can Link Transcription Elongation to Leukemia

Mol Cell. 2010 Feb 12;37(3):429-37. doi: 10.1016/j.molcel.2010.01.026.

Abstract

Chromosomal translocations involving the MLL gene are associated with infant acute lymphoblastic and mixed lineage leukemia. There are a large number of translocation partners of MLL that share very little sequence or seemingly functional similarities; however, their translocations into MLL result in the pathogenesis of leukemia. To define the molecular reason why these translocations result in the pathogenesis of leukemia, we purified several of the commonly occurring MLL chimeras. We have identified super elongation complex (SEC) associated with all chimeras purified. SEC includes ELL, P-TEFb, AFF4, and several other factors. AFF4 is required for SEC stability and proper transcription by poised RNA polymerase II in metazoans. Knockdown of AFF4 in leukemic cells shows reduction in MLL chimera target gene expression, suggesting that AFF4/SEC could be a key regulator in the pathogenesis of leukemia through many of the MLL partners.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Line, Tumor
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Drosophila Proteins / physiology
  • HSP70 Heat-Shock Proteins / metabolism
  • HeLa Cells
  • Heat-Shock Response
  • Histone-Lysine N-Methyltransferase
  • Homeobox A10 Proteins
  • Homeodomain Proteins / metabolism
  • Humans
  • Leukemia / genetics*
  • Molecular Sequence Data
  • Myeloid-Lymphoid Leukemia Protein / genetics*
  • Myeloid-Lymphoid Leukemia Protein / physiology
  • Positive Transcriptional Elongation Factor B / metabolism*
  • RNA Interference
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Repressor Proteins / physiology*
  • Sequence Alignment
  • Transcription, Genetic
  • Transcriptional Elongation Factors / metabolism*
  • Transcriptional Elongation Factors / physiology
  • Translocation, Genetic

Substances

  • AFF4 protein, human
  • Drosophila Proteins
  • ELL protein, human
  • HSP70 Heat-Shock Proteins
  • Homeobox A10 Proteins
  • Homeodomain Proteins
  • KMT2A protein, human
  • Repressor Proteins
  • Transcriptional Elongation Factors
  • homeobox protein HOXA9
  • HOXA10 protein, human
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase
  • Positive Transcriptional Elongation Factor B