Rac1 signaling protects monocytic AML cells expressing the MLL-AF9 oncogene from caspase-mediated apoptotic death

Apoptosis. 2013 Aug;18(8):963-79. doi: 10.1007/s10495-013-0842-6.


We investigated the relevance of signaling mechanisms regulated by the Ras-homologous GTPase Rac1 for survival of acute myeloid leukemia (AML) cells harbouring the MLL-AF9 oncogene due to t(9;11)(p21;q23) translocation. Monocytic MLL-AF9 expressing cells (MM6, THP-1) were hypersensitive to both small-molecule inhibitors targeting Rac1 (EHT 1864, NSC 23766) (IC50EHT ~12.5 μM) and lipid lowering drugs (lovastatin, atorvastatin) (IC50Lova ~7.5 μM) as compared to acute myelocytic leukemia (NOMO-1, HL60) and T cell leukemia (Jurkat) cells (IC50EHT >30 μM; IC50Lova >25 μM). Hypersensitivity of monocytic cells following Rac1 inhibition resulted from caspase-driven apoptosis as shown by profound activation of caspase-8,-9,-7,-3 and substantial (~90 %) decrease in protein expression of pro-survival factors (survivin, XIAP, p-Akt). Apoptotic death was preceded by S139-posphorylation of histone H2AX (γH2AX), a prototypical surrogate marker of DNA double-strand breaks (DSBs). Taken together, abrogation of Rac1 signaling causes DSBs in acute monocytic leukemia cells harbouring the MLL-AF9 oncogene, which, together with downregulation of survivin, XIAP and p-Akt, results in massive induction of caspase-driven apoptotic death. Apparently, Rac1 signaling is required for maintaining genetic stability and maintaining survival in specific subtypes of AML. Hence, targeting of Rac1 is considered a promising novel strategy to induce lethality in MLL-AF9 expressing AML.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis*
  • Caspases / genetics
  • Caspases / metabolism*
  • Cell Line, Tumor
  • DNA Breaks, Double-Stranded
  • Humans
  • Leukemia, Monocytic, Acute / enzymology
  • Leukemia, Monocytic, Acute / genetics
  • Leukemia, Monocytic, Acute / metabolism*
  • Leukemia, Monocytic, Acute / physiopathology
  • Monocytes / cytology
  • Monocytes / metabolism*
  • Myeloid-Lymphoid Leukemia Protein / genetics*
  • Myeloid-Lymphoid Leukemia Protein / metabolism
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Oncogene Proteins, Fusion / genetics*
  • Oncogene Proteins, Fusion / metabolism
  • Signal Transduction*
  • rac1 GTP-Binding Protein / genetics
  • rac1 GTP-Binding Protein / metabolism*


  • MLL-AF9 fusion protein, human
  • MLLT3 protein, human
  • Nuclear Proteins
  • Oncogene Proteins, Fusion
  • Myeloid-Lymphoid Leukemia Protein
  • Caspases
  • rac1 GTP-Binding Protein