title: Mer receptor tyrosine kinase is a therapeutic target in pre-B-cell acute lymphoblastic leukemia.
abstract: Acute lymphoblastic leukemia (ALL) is currently treated with an intense regimen of chemotherapy yielding cure rates near 85%. However, alterations to treatment strategies using available drugs are unlikely to provide significant improvement in survival or decrease therapy-associated toxicities. Here, we report ectopic expression of the Mer receptor tyrosine kinase in pre-B-cell ALL (B-ALL) cell lines and pediatric patient samples. Inhibition of Mer in B-ALL cell lines decreased activation of AKT and MAPKs and led to transcriptional changes, including decreased expression of antiapoptotic PRKCB gene and increase in proapoptotic BAX and BBC3 genes. Further, Mer inhibition promoted chemosensitization, decreased colony-forming potential in clonogenic assays, and delayed disease onset in a mouse xenograft model of leukemia. Our results identify Mer as a potential therapeutic target in B-ALL and suggest that inhibitors of Mer may potentiate lymphoblast killing when used in combination with chemotherapy. This strategy could reduce minimal residual disease and/or allow for chemotherapy dose reduction, thereby leading to improved event-free survival and reduced therapy-associated toxicity for patients with B-ALL. Additionally, Mer is aberrantly expressed in numerous other malignancies suggesting that this approach may have broad applications.
authors.affiliation: Department of Pediatrics, Section of Hematology, Oncology, and Bone Marrow Transplantation, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Rachel M A
authors.initials: RM
authors.lastname: Linger
authors.forename: Alisa B
authors.initials: AB
authors.lastname: Lee-Sherick
authors.forename: Deborah
authors.initials: D
authors.lastname: DeRyckere
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Cohen
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Jacobsen
authors.forename: Amy
authors.initials: A
authors.lastname: McGranahan
authors.forename: Luis N
authors.initials: LN
authors.lastname: Brandão
authors.forename: Amanda
authors.initials: A
authors.lastname: Winges
authors.forename: Kelly K
authors.initials: KK
authors.lastname: Sawczyn
authors.forename: Xiayuan
authors.initials: X
authors.lastname: Liang
authors.forename: Amy K
authors.initials: AK
authors.lastname: Keating
authors.forename: Aik Choon
authors.initials: AC
authors.lastname: Tan
authors.forename: H Shelton
authors.initials: HS
authors.lastname: Earp
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Graham
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D034741:RNA, Small Interfering / Q000494:pharmacology / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays; D000076202:c-Mer Tyrosine Kinase
chemical_list: D000970:Antineoplastic Agents; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; C097072:MERTK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase