Akt/foxo signaling pathway enforces the differentiation blockade in myeloid leukemias

Sykes, S. M., Lane, S. W., Bullinger, L., Demetrios, K., Yusuf, R., Saez, B., Ferraro, F., Mercier, F., Singh, H., Brumme, K. M., Acharya, S., Scholl, C., Tothova, Z., Attar, E., Froehling, S., DePinho, R. A., Gilliland, D. G., Armstrong, S. A. and Sca, D. T. (2011). Akt/foxo signaling pathway enforces the differentiation blockade in myeloid leukemias. In: ISEH 40th Annual Scientific Meeting, -, (S26-S26). 25 - 28 August 2011.

Author Sykes, S. M.
Lane, S. W.
Bullinger, L.
Demetrios, K.
Yusuf, R.
Saez, B.
Ferraro, F.
Mercier, F.
Singh, H.
Brumme, K. M.
Acharya, S.
Scholl, C.
Tothova, Z.
Attar, E.
Froehling, S.
DePinho, R. A.
Gilliland, D. G.
Armstrong, S. A.
Sca, D. T.
Title of paper Akt/foxo signaling pathway enforces the differentiation blockade in myeloid leukemias
Conference name ISEH 40th Annual Scientific Meeting
Conference location -
Conference dates 25 - 28 August 2011
Journal name Experimental Hematology   Check publisher's open access policy
Place of Publication Philadelphia, PA, United States
Publisher Elsevier
Publication Year 2011
Sub-type Published abstract
ISSN 0301-472X
1873-2399
Volume 39
Issue 8
Start page S26
End page S26
Total pages 1
Language eng
Formatted Abstract/Summary
Acute myeloid leukemia (AML) is a heterogeneous blood cancer comprised of different sub types that are categorized by genetic and molecular alterations. The complex heterogeneity of AMLs has made it difficult to identify molecular candidates that could
provide the basis for designing universal or broad spectrum target based AML therapies. Interestingly, the activity of the oncogenic kinase AKT has a bimodal distribution in AML, where 50% of patient samples display elevated AKT activity. We aimed to clarify the molecular mechanisms that contribute to the dichotomous pattern of AKT signaling in AML. AKT phosphorylates numerous substrates including  members of the FOXO family of transcription factors. FOXOs are exported from the nucleus and thereby inactivated upon AKT mediated phosphorylation. Therefore, we examined the cellular distribution of FOXOs in primary human AML samples. Of the 9
samples evaluated, 8 displayed a wide range of nuclear FOXO3 (10 70%). To determine the global status of FOXO activity in AML we used a hematopoietic specific gene signature of FOXO activity to perform hierarchical clustering analysis of gene expression data from a large cohort (n=436) of primary human AML samples. This analysis showed that AML stratifies into two distinct clusters based on FOXO activity (Cluster 1 representing lower FOXO (n=253) activity than Cluster 2 (n=183)) strongly  indicating that FOXOs play an important role in AML. To determine the functional relevance of FOXOs in AML, we introduced FOXO3 specific shRNA into both primary and cultured AML cells. Inhibition of FOXO3 expression resulted in diminished growth, enhanced differentiation and subsequent death of AML cells. Furthermore, ablation of FoxO1/3/4 in a murine model of AML (driven by MLL AF9) resulted in decreased leukemic burden (p<0.0001), increased survival (p=0.0009) and reduced leukemia initiating cell activity (p=0.0007) in vivo. Although deletion of FoxO1/3/4 extended latency, the majority of animals transplanted with leukemia null for FoxO1/3/4
eventually develop overt AML. Therefore, we predicted that a molecular switch exists that allows leukemia cells to survive FOXO inactivation. Examination of oncogenic signaling pathways associated with AML revealed that the stress  activated kinase JNK and its downstream substrate c  JUN are consistently activated in murine AMLs null  for FOXOs. Further analysis of the aforementioned  436 primary AML sample gene expression data  revealed that AMLs that display lower FOXO activity exhibit elevated c JUN expression (cluster 1) and vice  versa (p<0.0001). Remarkably,  pharmacological inhibition of JNK cooperates with FOXO inhibition to  induce apoptosis in murine and human AML cells. These data identify previously  unrecognized roles of  AKT, FOXOs, JNK and cJUN in AML and unveil a signaling  network that could potentially have  diagnostic and therapeutic implications. 
Q-Index Code EX
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Conference Paper
Collection: School of Medicine Publications
 
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