AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias

Stephen M. Sykes; Steven W. Lane; Lars Bullinger; Demetrios Kalaitzidis; Rushdia Yusuf; Borja Saez; Francesca Ferraro; Francois Mercier; Harshabad Singh; Kristina M. Brumme; Sanket S. Acharya; Claudia Schöll; Zuzana Tothova; Eyal C. Attar; Stefan Fröhling; Ronald A. Depinho; Scott A. Armstrong; D. Gary Gilliland; David T. Scadden

doi:10.1016/j.cell.2011.07.032

AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias

Stephen M. Sykes, Steven W. Lane, Lars Bullinger, Demetrios Kalaitzidis, Rushdia Yusuf, Borja Saez, Francesca Ferraro, Francois Mercier, Harshabad Singh, Kristina M. Brumme, Sanket S. Acharya, Claudia Schöll, Zuzana Tothova, Eyal C. Attar, Stefan Fröhling, Ronald A. Depinho, Scott A. Armstrong, D. Gary Gilliland, David T. Scadden

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233 Scopus citations

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. PaperClip:

Original language	English
Pages (from-to)	697-708
Number of pages	12
Journal	Cell
Volume	146
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2011.07.032
State	Published - Sep 2 2011

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10.1016/j.cell.2011.07.032

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Sykes, S. M., Lane, S. W., Bullinger, L., Kalaitzidis, D., Yusuf, R., Saez, B., Ferraro, F., Mercier, F., Singh, H., Brumme, K. M., Acharya, S. S., Schöll, C., Tothova, Z., Attar, E. C., Fröhling, S., Depinho, R. A., Armstrong, S. A., Gilliland, D. G., & Scadden, D. T. (2011). AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias. Cell, 146(5), 697-708. https://doi.org/10.1016/j.cell.2011.07.032

@article{4cf61d5b70414e739e2a51b3f47fa1f3,

title = "AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias",

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. PaperClip:",

author = "Sykes, {Stephen M.} and Lane, {Steven W.} and Lars Bullinger and Demetrios Kalaitzidis and Rushdia Yusuf and Borja Saez and Francesca Ferraro and Francois Mercier and Harshabad Singh and Brumme, {Kristina M.} and Acharya, {Sanket S.} and Claudia Sch{\"o}ll and Zuzana Tothova and Attar, {Eyal C.} and Stefan Fr{\"o}hling and Depinho, {Ronald A.} and Armstrong, {Scott A.} and Gilliland, {D. Gary} and Scadden, {David T.}",

note = "Funding Information: We would like to thank Dr. Christine Ragu, Dr. Andrew Lane, and Dr. David Sykes for critically reading the manuscript and providing valuable suggestions. We would also like to thank Dr. Kira Gritsman and Dr. Michael Kharas for donating the MSCV-IRES-GFP-myr-Akt construct. We would also like to thank M. Milsom for donating the LoxP-STOP-LoxP-hCD34 expression plasmid. S.M.S. was supported by NHLBI 5T32HL007623-24. L.B. was supported by the Deutsche Forschungsgemeinschaft (Heisenberg-Stipendium BU 1339/3-1). R.Y. is supported by the Leukemia and Lymphoma Society and the Alex Lemonade Stand Foundation. B.S. is supported by the Chamber of Industry and Commerce of the Government of Spain. F.F. is supported by NHLBI U01HL100402. R.A.D. was supported by NCI U01CA141508. S.A.A. was supported by the Leukemia and Lymphoma Society and NCI CA140575. D.T.S. is supported by the NIH NHLBI HL097794, HL097748, and HL100402 and NIDDK DK050234, the Ellison Foundation, and the Harvard Stem Cell Institute. D.G.G. is a full-time employee of Merck & Company, Inc. ",

year = "2011",

month = sep,

day = "2",

doi = "10.1016/j.cell.2011.07.032",

language = "English",

volume = "146",

pages = "697--708",

journal = "Cell",

issn = "0092-8674",

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Sykes, SM, Lane, SW, Bullinger, L, Kalaitzidis, D, Yusuf, R, Saez, B, Ferraro, F, Mercier, F, Singh, H, Brumme, KM, Acharya, SS, Schöll, C, Tothova, Z, Attar, EC, Fröhling, S, Depinho, RA, Armstrong, SA, Gilliland, DG & Scadden, DT 2011, 'AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias', Cell, vol. 146, no. 5, pp. 697-708. https://doi.org/10.1016/j.cell.2011.07.032

TY - JOUR

T1 - AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias

AU - Sykes, Stephen M.

AU - Lane, Steven W.

AU - Bullinger, Lars

AU - Kalaitzidis, Demetrios

AU - Yusuf, Rushdia

AU - Saez, Borja

AU - Ferraro, Francesca

AU - Mercier, Francois

AU - Singh, Harshabad

AU - Brumme, Kristina M.

AU - Acharya, Sanket S.

AU - Schöll, Claudia

AU - Tothova, Zuzana

AU - Attar, Eyal C.

AU - Fröhling, Stefan

AU - Depinho, Ronald A.

AU - Armstrong, Scott A.

AU - Gilliland, D. Gary

AU - Scadden, David T.

N1 - Funding Information: We would like to thank Dr. Christine Ragu, Dr. Andrew Lane, and Dr. David Sykes for critically reading the manuscript and providing valuable suggestions. We would also like to thank Dr. Kira Gritsman and Dr. Michael Kharas for donating the MSCV-IRES-GFP-myr-Akt construct. We would also like to thank M. Milsom for donating the LoxP-STOP-LoxP-hCD34 expression plasmid. S.M.S. was supported by NHLBI 5T32HL007623-24. L.B. was supported by the Deutsche Forschungsgemeinschaft (Heisenberg-Stipendium BU 1339/3-1). R.Y. is supported by the Leukemia and Lymphoma Society and the Alex Lemonade Stand Foundation. B.S. is supported by the Chamber of Industry and Commerce of the Government of Spain. F.F. is supported by NHLBI U01HL100402. R.A.D. was supported by NCI U01CA141508. S.A.A. was supported by the Leukemia and Lymphoma Society and NCI CA140575. D.T.S. is supported by the NIH NHLBI HL097794, HL097748, and HL100402 and NIDDK DK050234, the Ellison Foundation, and the Harvard Stem Cell Institute. D.G.G. is a full-time employee of Merck & Company, Inc.

PY - 2011/9/2

Y1 - 2011/9/2

N2 - 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. PaperClip:

AB - 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. PaperClip:

UR - http://www.scopus.com/inward/record.url?scp=80052276420&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2011.07.032

DO - 10.1016/j.cell.2011.07.032

M3 - Article

C2 - 21884932

AN - SCOPUS:80052276420

SN - 0092-8674

VL - 146

SP - 697

EP - 708

JO - Cell

JF - Cell

IS - 5

ER -

AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias

Abstract

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