scholarly journals Exploiting an Asp-Glu “switch” in glycogen synthase kinase 3 to design paralog-selective inhibitors for use in acute myeloid leukemia

2018 ◽  
Vol 10 (431) ◽  
pp. eaam8460 ◽  
Author(s):  
Florence F. Wagner ◽  
Lina Benajiba ◽  
Arthur J. Campbell ◽  
Michel Weïwer ◽  
Joshua R. Sacher ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Selective Inhibitors ◽  
Acute Myeloid

Frat2 mediates the oncogenic activation of Rac by MLL fusions

Blood ◽  
2012 ◽  
Vol 120 (24) ◽  
pp. 4819-4828 ◽  
Author(s):  
Vanessa Walf-Vorderwülbecke ◽  
Jasper de Boer ◽  
Sarah J. Horton ◽  
Renée van Amerongen ◽  
Natalie Proost ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Signaling Mechanism ◽  
Rac Gtpases ◽  
Increased Sensitivity ◽  
Canonical Wnt ◽  
Acute Myeloid

Abstract Mixed lineage leukemia (MLL) fusion genes arise from chromosomal translocations and induce acute myeloid leukemia through a mechanism involving transcriptional deregulation of differentiation and self-renewal programs. Progression of MLL-rearranged acute myeloid leukemia is associated with increased activation of Rac GTPases. Here, we demonstrate that MLL fusion oncogenes maintain leukemia-associated Rac activity by regulating Frat gene expression, specifically Frat2. Modulation of FRAT2 leads to concomitant changes in Rac activity, and transformation of Frat knockout hematopoietic progenitor cells by MLL fusions results in leukemias displaying reduced Rac activation and increased sensitivity to chemotherapeutic drugs. FRAT2 activates Rac through a signaling mechanism that requires glycogen synthase kinase 3 and DVL. Disruption of this pathway abrogates the leukemogenic activity of MLL fusions. This suggests a rationale for the paradoxical requirement of canonical Wnt signaling and glycogen synthase kinase 3 activity for MLL fusion oncogenicity and identifies novel therapeutic targets for this disease.

scholarly journals A Novel Glycogen Synthase Kinase-3 Inhibitor Optimized for Acute Myeloid Leukemia Differentiation Activity

2016 ◽  
Vol 15 (7) ◽  
pp. 1485-1494 ◽  
Author(s):  
Sophia Hu ◽  
Masumi Ueda ◽  
Lindsay Stetson ◽  
James Ignatz-Hoover ◽  
Stephen Moreton ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Acute Myeloid

scholarly journals Evaluation of Improved Glycogen Synthase Kinase-3α Inhibitors in Models of Acute Myeloid Leukemia

2015 ◽  
Vol 58 (22) ◽  
pp. 8907-8919 ◽  
Author(s):  
Theresa Neumann ◽  
Lina Benajiba ◽  
Stefan Göring ◽  
Kimberly Stegmaier ◽  
Boris Schmidt
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Acute Myeloid

Combined effects of FLT3 and NF-κB selective inhibitors on acute myeloid leukemia in vivo

2011 ◽  
Vol 26 (1) ◽  
pp. 35-43 ◽  
Author(s):  
Chunmei Wang ◽  
Jie Lu ◽  
Yumei Wang ◽  
Songting Bai ◽  
Yingchao Wang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Combined Effects ◽  
Selective Inhibitors ◽  
Acute Myeloid

scholarly journals Selective Inhibitors of Histone Deacetylases 1 and 2 Synergize with Azacitidine in Acute Myeloid Leukemia

PLoS ONE ◽  
2017 ◽  
Vol 12 (1) ◽  
pp. e0169128 ◽  
Author(s):  
Chengyin Min ◽  
Nathan Moore ◽  
Jeffrey R. Shearstone ◽  
Steven N. Quayle ◽  
Pengyu Huang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Histone Deacetylases ◽  
Myeloid Leukemia ◽  
Selective Inhibitors ◽  
Acute Myeloid

6-Heteroaryl-pyrazolo[3,4-b]pyridines: potent and selective inhibitors of glycogen synthase kinase-3 (GSK-3)

2003 ◽  
Vol 13 (18) ◽  
pp. 3059-3062 ◽  
Author(s):  
Jason Witherington ◽  
Vincent Bordas ◽  
Alessandra Gaiba ◽  
Antoinette Naylor ◽  
Anthony D. Rawlings ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Selective Inhibitors
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