Mer receptor tyrosine kinase is a therapeutic target in pre–B-cell acute lymphoblastic leukemia

Rachel M.A. Linger, Alisa B. Lee-Sherick, Deborah DeRyckere, Rebecca A. Cohen, Kristen M. Jacobsen, Amy McGranahan, Luis N. Brandão, Amanda Winges, Kelly K. Sawczyn, Xiayuan Liang, Amy K. Keating, Aik Choon Tan, H. Shelton Earp, Douglas K. Graham

Research output: Contribution to journalArticle

32 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1599-1609
Number of pages11
JournalBlood
Volume122
Issue number9
DOIs
Publication statusPublished - 2013 Jan 1

    Fingerprint

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Linger, R. M. A., Lee-Sherick, A. B., DeRyckere, D., Cohen, R. A., Jacobsen, K. M., McGranahan, A., Brandão, L. N., Winges, A., Sawczyn, K. K., Liang, X., Keating, A. K., Tan, A. C., Earp, H. S., & Graham, D. K. (2013). Mer receptor tyrosine kinase is a therapeutic target in pre–B-cell acute lymphoblastic leukemia. Blood, 122(9), 1599-1609. https://doi.org/10.1182/blood-2013-01-478156