The intersection of genetic and chemical genomic screens identifies GSK-3α as a target in human acute myeloid leukemia.
Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. Long-term survival of patients with AML has changed little over the past decade, necessitating the identification and validation of new AML targets. Integration of genomic approaches with small-molecule and genetically based high-throughput screening holds the promise of improved discovery of candidate targets for cancer therapy. Here, we identified a role for glycogen synthase kinase 3α (GSK-3α) in AML by performing 2 independent small-molecule library screens and an shRNA screen for perturbations that induced a differentiation expression signature in AML cells. GSK-3 is a serine-threonine kinase involved in diverse cellular processes, including differentiation, signal transduction, cell cycle regulation, and proliferation. We demonstrated that specific loss of GSK-3α induced differentiation in AML by multiple measurements, including induction of gene expression signatures, morphological changes, and cell surface markers consistent with myeloid maturation. GSK-3α-specific suppression also led to impaired growth and proliferation in vitro, induction of apoptosis, loss of colony formation in methylcellulose, and anti-AML activity in vivo. Although the role of GSK-3β has been well studied in cancer development, these studies support a role for GSK-3α in AML.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Division of Hematology/Oncology, Children’s Hospital Boston, Boston 02215, Massachusetts, USA.
Versha
V
Banerji
Stacey M
SM
Frumm
Kenneth N
KN
Ross
Loretta S
LS
Li
Anna C
AC
Schinzel
Cynthia K
CK
Hahn
Rose M
RM
Kakoza
Kwan T
KT
Chow
Linda
L
Ross
Gabriela
G
Alexe
Nicola
N
Tolliday
Haig
H
Inguilizian
Ilene
I
Galinsky
Richard M
RM
Stone
Daniel J
DJ
DeAngelo
Giovanni
G
Roti
Jon C
JC
Aster
William C
WC
Hahn
Andrew L
AL
Kung
Kimberly
K
Stegmaier
D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology* / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism*; D034622:RNA Interference; D013678:Technology, Pharmaceutical; D020298:U937 Cells
D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha