Abstract
MAPK interacting kinase (MNK), a downstream effector of mitogen-activated protein kinase (MAPK) pathways, activates eukaryotic translation initiation factor 4E (eIF4E) and plays a key role in the mRNA translation of mitogenic and antiapoptotic genes in acute myeloid leukemia (AML) cells. We examined the antileukemic properties of a novel MNK inhibitor, SEL201. Our studies provide evidence that SEL201 suppresses eIF4E phosphorylation on Ser209 in AML cell lines and in primary patient-derived AML cells. Such effects lead to growth inhibitory effects and leukemic cell apoptosis, as well as suppression of leukemic progenitor colony formation. Combination of SEL201 with 5’-azacytidine or rapamycin results in synergistic inhibition of AML cell growth. Collectively, these results suggest that SEL201 has significant antileukemic activity and further underscore the relevance of the MNK pathway in leukemogenesis.
Highlights
Acute myeloid leukemia (AML) is an aggressive hematological malignancy with relatively limited therapeutic options [1]
MAPK-interacting kinases 1 and 2 (MNK1/2) phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) at serine 209 triggers increased mRNA translation of mitogenic mRNAs that promote proliferation, cell cycle progression, and pro-survival processes [12,13,14,15]. eIF4E has been found to be overexpressed in a wide variety of human malignancies [16,17,18,19,20] and eIF4E phosphorylation on serine 209 is strongly associated with its transforming capacity [21, 13]
We examined the effects of SEL201 on eIF4E phosphorylation in acute myeloid leukemia (AML) cells
Summary
Acute myeloid leukemia (AML) is an aggressive hematological malignancy with relatively limited therapeutic options [1]. Abnormal activation of multiple signalling pathways, including mitogen-activated protein kinase (MAPK) pathways, is key in the pathogenesis and pathophysiology of AML. These pathways regulate different cellular processes including leukemic cell proliferation and survival in response to a variety of signals [2,3,4,5]. MAPK-interacting kinases 1 and 2 (MNK1/2) are downstream effectors of MAPK pathways and regulate multiple cellular processes through phosphorylation/ activation of the eukaryotic translation initiation factor 4E (eIF4E) [6,7,8,9], a key component of the translationinitiation complex [10, 11]. Given that MNKmediated eIF4E phosphorylation strongly contributes to tumorigenesis, lymphomagenesis, and tumor metastasis while being dispensable for development, pharmacological MNK1/2 inhibition may represent an attractive strategy for the treatment of leukemias [24, 21, 12]
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