AKT/FOXO Signaling Enforces Reversible Differentiation Blockade in Myeloid Leukemias

被引：272

作者：

Sykes, Stephen M. ^{[1
,2
,3
]}

Lane, Steven W. ^{[4
]}

Bullinger, Lars ^{[9
]}

Kalaitzidis, Demetrios ^{[4
]}

Yusuf, Rushdia ^{[1
,2
,3
]}

Saez, Borja ^{[1
,2
,3
]}

Ferraro, Francesca ^{[1
,2
,3
]}

Mercier, Francois ^{[1
,2
,3
]}

Singh, Harshabad ^{[1
,2
]}

Brumme, Kristina M. ^{[4
]}

Acharya, Sanket S. ^{[1
,2
,3
]}

Schoell, Claudia ^{[9
]}

Tothova, Zuzana ^{[5
]}

Attar, Eyal C. ^{[1
,2
]}

Froehling, Stefan ^{[9
]}

DePinho, Ronald A. ^{[6
,7
,8
]}

Armstrong, Scott A. ^{[4
]}

Gilliland, D. Gary ^{[10
]}

Scadden, David T. ^{[1
,2
,3
]}

机构：

[1] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA

[2] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA

[3] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA

[4] Harvard Univ, Sch Med, Div Hematol Oncol, Childrens Hosp Boston, Boston, MA 02115 USA

[5] Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA 02115 USA

[6] Harvard Univ, Sch Med, Belfer Inst Appl Canc Sci, Dept Med Oncol, Boston, MA 02115 USA

[7] Harvard Univ, Sch Med, Belfer Inst Appl Canc Sci, Dept Med, Boston, MA 02115 USA

[8] Harvard Univ, Sch Med, Dept Genet, Dana Farber Canc Inst, Boston, MA 02115 USA

[9] Univ Hosp Ulm, Dept Internal Med 3, D-89081 Ulm, Germany

[10] Merck Res Labs, N Wales, PA 19454 USA

来源：

CELL | 2011年 / 146卷 / 05期

关键词：

HEMATOPOIETIC STEM-CELLS; PROTEIN-KINASE-B; FORKHEAD TRANSCRIPTION FACTOR; JUN ACTIVATION DOMAIN; OXIDATIVE STRESS; AKT PHOSPHORYLATION; TUMOR SUPPRESSORS; INITIATING CELLS; INSULIN; FOXO;

D O I：

10.1016/j.cell.2011.07.032

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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 similar to 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.

引用

页码：697 / 708

页数：12

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