AKT/FOXO Signaling Enforces Reversible Differentiation Blockade in Myeloid Leukemias

Cell. 2011 Sep 2;146(5):697-708. doi: 10.1016/j.cell.2011.07.032.

Abstract

AKT activation is associated with many malignancies, where AKT acts, in part, by inhibiting FOXO tumor suppressors. We show a converse role for AKT/FOXOs in acute myeloid leukemia (AML). Rather than decreased FOXO activity, we observed that FOXOs are active in ∼40% of AML patient samples regardless of genetic subtype. We also observe this activity in human MLL-AF9 leukemia allele-induced AML in mice, where either activation of Akt or compound deletion of FoxO1/3/4 reduced leukemic cell growth, with the latter markedly diminishing leukemia-initiating cell (LIC) function in vivo and improving animal survival. FOXO inhibition resulted in myeloid maturation and subsequent AML cell death. FOXO activation inversely correlated with JNK/c-JUN signaling, and leukemic cells resistant to FOXO inhibition responded to JNK inhibition. These data reveal a molecular role for AKT/FOXO and JNK/c-JUN in maintaining a differentiation blockade that can be targeted to inhibit leukemias with a range of genetic lesions.

Publication types

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

MeSH terms

  • Animals
  • Antigens, CD34 / metabolism
  • Apoptosis
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / metabolism
  • Cell Differentiation
  • Cell Line, Tumor
  • Cells, Cultured
  • Disease Models, Animal
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors / metabolism*
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Leukemia, Myeloid / metabolism*
  • Leukemia, Myeloid / pathology*
  • Mice
  • Neoplastic Stem Cells / cytology
  • Neoplastic Stem Cells / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction*

Substances

  • Antigens, CD34
  • FOXO3 protein, human
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • Proto-Oncogene Proteins c-akt
  • JNK Mitogen-Activated Protein Kinases