AKT/FOXO Signaling Enforces Reversible Differentiation Blockade in Myeloid Leukemias

SummaryAKT 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.PaperClip To listen to this audio, enable JavaScript on your browser. However, you can download and play the audio by clicking on the icon belowHelp with MP3 filesOptionsDownload audio (2908 K)

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (323 K)Download as PowerPoint slideHighlights► Unlike other cancers, acute myeloid leukemia (AML) is maintained by low AKT and high FOXO ► FOXOs are required to maintain leukemia-initiating cells (LICs) ► Resistance to FOXO depletion is mediated by JNK/c-JUN signaling ► Elevated FOXOs present in 40% of AML patients regardless of genetic subtype