Journal
LEUKEMIA
Volume 27, Issue 11, Pages 2118-2128Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2013.89
Keywords
AML; SYK; mTOR; RPS6; 4E-BP1; MAPK
Categories
Funding
- National Cancer Institute [R01 CA140292]
- American Cancer Society
- Starr Cancer Consortium and Project Cupid
Ask authors/readers for more resources
Spleen tyrosine kinase (SYK) was recently identified as a new target in acute myeloid leukemia (AML); however, its mechanistic role in this disease is poorly understood. Based on the known interaction between SYK and mammalian target of rapamycin (mTOR) signaling in lymphoma, we hypothesized that SYK may regulate mTOR signaling in AML. Both small-molecule inhibition of SYK and SYK-directed shRNA suppressed mTOR and its downstream signaling effectors, as well as its upstream activator, AKT. Moreover, the inhibition of multiple nodes of the phosphatidylinositol 3'- kinase (PI3K) signaling pathway enhanced the effects of SYK suppression on AML cell viability and differentiation. Evaluation of the collateral mitogen-activated protein kinase (MAPK) pathway revealed a heterogeneous response to SYK inhibition in AML with downregulation of MEK and extracellular signal-regulated kinase (ERK) phosphorylation in some AML cell lines but a paradoxical increase in MEK/ERK phosphorylation in RAS-mutated AML. These studies reveal SYK as a regulator of mTOR and MAPK signaling in AML and demonstrate that inhibition of PI3K pathway activity enhances the effects of SYK inhibition on AML cell viability and differentiation.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available