The treatment of AML remains to be a challenge due to the high rates of resistance and relapse experienced by patients after initial therapy. The MAPK-interacting kinases 1 and 2 (MNK1/2) have generated increasing interest as therapeutic targets for AML due to their critical role in malignant hematopoietic transformation via regulation of the eukaryotic translation initiation factor 4E (eIF4E). However, pharmacological MNK1/2 inhibition in AML has only yielded limited pre-clinical responses thus far, mainly due to the lack of selective and efficacious inhibitors of MNK1/2. We evaluated the therapeutic potential of the highly-selective MNK1/2 inhibitor Tomivosertib on AML cells. In addition, to identify new effectors of the MNK1/2 pathway that could be therapeutically targeted, a MS-based phosphoproteomic screen was performed on AML cells treated with Tomivosertib. Tomivosertib was highly effective at blocking eIF4E phosphorylation on serine 209 in AML cells. Such inhibitory effects correlated with dose-dependent suppression of cellular viability and leukemic progenitor colony formation. Moreover, combination of Tomivosertib and Venetoclax resulted in synergistic anti-leukemic responses in AML cell lines. Our phosphoproteomic studies identified the Enhancer of mRNA Decapping Protein 4 (EDC4) and B-Cell CLL/Lymphoma 7 Protein Family Member C (BCL7C) as putative MNK1/2 targets. These proteins are involved in the regulation of mRNA decapping and chromatin remodelling, respectively, suggesting a potentially novel role for MNK1/2 in these processes. Overall, these findings demonstrate that Tomivosertib exhibits potent anti-leukemic properties on AML cells and support the development of clinical translational efforts involving the use of this drug, alone or in combination with other therapies for the treatment of AML. Future studies are required to confirm the MNK1/2-mediated phosphorylation of the putative substrates identified in this study. This work will further expand our current understanding of MNK1/2 cellular signaling and may ultimately lead to the development of more effective therapeutic strategies for the treatment of AML.

Creator

• Suarez Palacios, Milagros Melanie

DOI

• https://doi.org/10.21985/n2-d57s-c112

Subject

• Molecular biology
• Biology
• Biochemistry

Language

• en

Alternate Identifier

• etdadmin_upload_845430
• http://dissertations.umi.com/northwestern:15772

Date created

• 2021-01-01

Resource type

• Dissertation

Rights statement

• In Copyright