DNA-damage-induced differentiation of leukaemic cells as an anti-cancer barrier ( Nature 2014, doi:10.1038/nature13483)

報告日期: 2014/10/24
報告時間: 3:10/4:00
報告學生: 鄭慧卿
講評老師: 黃溫雅
附件下載: 下載[1420-1412163492-1.pdf] 

DNA-damage-induced differentiation of leukaemic cells as an anti-cancer barrier

Santos MA,et al.

Nature 514, 107-111, 2014

 

Speaker: Hui-Ching Cheng                                      Time: 2014/10/24 15:10 PM

Commentator: Dr. Wenya Huang                     Place: Room 602

Abstract

Leukaemias with MLL gene translocations are associated with acute myeloid leukaemias (AML) in infants1.  Histone methyltransferase MLL4, one of the MLL family members, is known as a tumor suppressor in B-cell lymphoma2.  However, up to now, the detailed mechanism of MLL4 controlling leukaemias and its downstream target genes are still unknown.  In this paper, the authors conducted MLL4 conditional knockout in stem and progenitor cells by crossing MLL4f/f mice with transgenic mice expressing interferon-inducible DNA recombinase MxCre.  Significantly, increased haematopoietic stem cells with attenuated self-renewal capacity and mature myeloid cells were detected in MLL4-/- mice, whereas lymphopoiesis was reduced by MLL4 gene ablation.  Previous studies have indicated that MLL1 and AF9 gene translocation in mice is an experimental model to mimic AML.  Upon MLL-AF9 oncogene induction, deletion of MLL4 reduced leukaemia blasts, increased myeloid differentiation and maturation via p21 activation, and enhanced mouse survival, indicating that MLL4 is essential for MLL-AF9-induced leukaemia.  Moreover, MLL4 stimulated glutathione detoxification and FOXO signaling pathway for regulating oxidative stress response.  Loss of MLL4 increased reactive oxygen species (ROS) and DNA damage levels, as monitored by the increased levels of phosphorylated Kap1, and amelioration of MLL-AF9-induced leukaemia.  Ectopic overexpression of FOXO3 downregulated ROS levels in cells.  The authors demonstrated that FOXO3 is one of MLL4 target genes.  Furthermore, by generating double-strand breaks using a restriction enzyme, the authors determined that DNA damage-induced myeloid differentiation is mediated dependently or independently by ROS.  In conclusion, these findings suggest that MLL-fusion oncogene-induced activation of tumor suppressors such as MLL4 enhances AML development via inhibiting myeloid cell differentiation and maturation.

 

References

  1. Krivtsov AVand Armstrong SA.MLL translocations, histone modifications and leukaemia stem-cell development.Nat Rev Cancer 7, 823-833, 2007.
  2. Morin RD,et al.Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature 476, 298-303, 2011.