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.
Bibliographical noteFunding Information:
The authors thank Dr Stephen Hunger and the Children’s Oncology Group (grants CA98543 and CA114766) for providing E2A-PBX1+ samples and the University of Colorado Cancer Center Core Facilities (grant P30CA046934; flow cytometry, genomics and microarray, real-time PCR) for expert technical assistance.
This work was supported by grants from the American Academy of Pediatrics, the American Pediatric Society, and the National Institute of Child Health and Human Development (K12-HD000850) (A.B.L.-S. is a Fellow of their Pediatric Scientist Development Program); by the American Cancer Society (RSG-08-291-01-LIB) and National Institutes of Health (R01CA137078; D.K.G.), by Gabrielle’s Angel Foundation for Cancer Research (#030; D.K.G.), by the Damon Runyon Cancer Research Foundation (CI-39-07; D.K.G.), and by the Brent Eley Foundation (A.K.K.).
© 2013 by The American Society of Hematology.
ASJC Scopus subject areas
- Cell Biology