Mer Receptor Tyrosine Kinase is a Novel Therapeutic Target in Pediatric B-cell Acute Lymphoblastic Leukemia

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2009 Aug 1

PMID 19643988

Citations 17

Authors

Rachel M A Linger

Deborah DeRyckere

Luis Brandao

Kelly K Sawczyn

Kristen M Jacobsen

Xiayuan Liang

Amy K Keating

Douglas K Graham

Affiliations

Soon will be listed here.

Abstract

Acute lymphoblastic leukemia (ALL) is currently treated with an intense regimen of chemotherapy yielding cure rates near 80%. However, additional changes using available drugs are unlikely to provide significant improvement in survival. New therapies are warranted given the risk of severe therapy-associated toxicities including infertility, organ damage, and secondary malignancy. Here, we report ectopic expression of the receptor tyrosine kinase Mer in pediatric B-cell ALL. Inhibition of Mer prevented Erk 1/2 activation, increased the sensitivity of B-ALL cells to cytotoxic agents in vitro by promoting apoptosis, and delayed disease onset in a mouse model of leukemia. In addition, we discovered cross-talk between the Mer and mammalian target of rapamycin (mTOR) signaling pathways. Our results identify Mer as a novel therapeutic target in ALL and suggest that inhibitors of Mer will interact synergistically with currently used therapies. This strategy may allow for dose reduction resulting in decreased toxicity and increased survival rates. Mer is aberrantly expressed in numerous other malignancies suggesting that this approach may have broad applications.

Citing Articles

EXT1, Regulated by MiR-665, Promotes Cell Apoptosis via ERK1/2 Signaling Pathway in Acute Lymphoblastic Leukemia.

Liu N, Huang X, Liu S, Lu Y Med Sci Monit. 2019; 25:6491-6503.

PMID: 31465316 PMC: 6733154. DOI: 10.12659/MSM.918295.

MiR-193b, downregulated in Ewing Sarcoma, targets the ErbB4 oncogene to inhibit anchorage-independent growth.

Moore C, Parrish J, Jedlicka P PLoS One. 2017; 12(5):e0178028.

PMID: 28542597 PMC: 5436853. DOI: 10.1371/journal.pone.0178028.

TAM receptor tyrosine kinase function and the immunopathology of liver disease.

Mukherjee S, Wilhelm A, Antoniades C Am J Physiol Gastrointest Liver Physiol. 2016; 310(11):G899-905.

PMID: 26867565 PMC: 4935487. DOI: 10.1152/ajpgi.00382.2015.

Discovery of Mer kinase inhibitors by virtual screening using Structural Protein-Ligand Interaction Fingerprints.

Da C, Stashko M, Jayakody C, Wang X, Janzen W, Frye S Bioorg Med Chem. 2015; 23(5):1096-101.

PMID: 25638502 PMC: 4339536. DOI: 10.1016/j.bmc.2015.01.001.

Variable expression of PIK3R3 and PTEN in Ewing Sarcoma impacts oncogenic phenotypes.

Niemeyer B, Parrish J, Spoelstra N, Joyal T, Richer J, Jedlicka P PLoS One. 2015; 10(1):e0116895.

PMID: 25603314 PMC: 4300218. DOI: 10.1371/journal.pone.0116895.

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