t(4;11) leukemias display addiction to MLL-AF4 but not to AF4-MLL

Leuk Res. 2011 Mar;35(3):305-9. doi: 10.1016/j.leukres.2010.08.011. Epub 2010 Sep 25.

Abstract

The most frequent MLL-gene rearrangement found in leukemia is a reciprocal translocation with AF4 on chromosome 4 resulting in the formation of the MLL-AF4 and the AF4-MLL fusion genes. The oncogenic role of MLL-AF4 is documented but the significance of the reciprocal product - AF4-MLL in leukemia is less clear. In the human leukemia cell lines - RS4;11 and SEMK2-M1, both of which express MLL-AF4 and AF4-MLL, we knocked down the expression of AF4-MLL using siRNA. Loss of AF4-MLL had no effect on the growth of either RS4;11 or SEMK2-M1 cells. Furthermore, in SEMK2-M1 cells there were no changes in cell cycle or apoptosis with loss of AF4-MLL. In contrast, knockdown of MLL-AF4 significantly inhibited growth of both RS4;11 and SEMK2-M1. Additionally, in SEMK2-M1 cells, loss of MLL-AF4 led to G2/M cell cycle arrest and increased apoptosis. Overall, these results demonstrate that in t(4;11) leukemia, the MLL-AF4 fusion protein is critical for leukemia cell proliferation and survival while the AF4-MLL fusion product is dispensable.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis*
  • Blotting, Western
  • Cell Cycle
  • Cell Proliferation
  • Chromosomes, Human, Pair 11 / genetics*
  • Chromosomes, Human, Pair 4 / genetics*
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / genetics*
  • Histone-Lysine N-Methyltransferase
  • Humans
  • Leukemia / genetics*
  • Leukemia / pathology
  • Myeloid-Lymphoid Leukemia Protein / antagonists & inhibitors
  • Myeloid-Lymphoid Leukemia Protein / genetics*
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / genetics*
  • Oncogene Proteins, Fusion / antagonists & inhibitors
  • Oncogene Proteins, Fusion / genetics*
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcriptional Elongation Factors
  • Translocation, Genetic / genetics*
  • Tumor Cells, Cultured

Substances

  • DNA-Binding Proteins
  • KMT2A protein, human
  • MLL-AF4 fusion protein, human
  • Nuclear Proteins
  • Oncogene Proteins, Fusion
  • RNA, Messenger
  • RNA, Small Interfering
  • Transcriptional Elongation Factors
  • Myeloid-Lymphoid Leukemia Protein
  • AFF1 protein, human
  • Histone-Lysine N-Methyltransferase