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Updated: Aug 5, 2026
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
Lymphoblastic leukemia/lymphoma in mice overexpressing the Mer (MerTK) receptor tyrosine kinase
A K Keating1, D B Salzberg, S Sather
1Department of Pediatrics, University of Colorado at Denver and Health Sciences Center, Denver, CO 80045, USA.
Abstract:
Mer (MerTK) is a receptor tyrosine kinase important in platelet aggregation, as well as macrophage cytokine secretion and clearance of apoptotic cells. Mer is not normally expressed in thymocytes or lymphocytes; however, ectopic Mer RNA transcript and protein expression is found in a subset of acute lymphoblastic leukemia cell lines and patient samples, suggesting a role in leukemogenesis. To investigate the oncogenic potential of Mer in vivo, we created a transgenic mouse line (Mer(Tg)) that expresses Mer in the hematopoietic lineage under control of the Vav promoter. Ectopic expression and activation of the transgenic Mer protein was demonstrated in lymphocytes and thymocytes of the Mer(Tg) mice. At 12-24 months of age, greater than 55% of the Mer(Tg) mice, compared to 12% of the wild type, developed adenopathy, hepatosplenomegaly, and circulating lymphoblasts. Histopathological analysis and flow cytometry were consistent with T-cell lymphoblastic leukemia/lymphoma. Mer may contribute to leukemogenesis by activation of Akt and ERK1/2 anti-apoptotic signals, which were upregulated in Mer(Tg) mice. Additionally, a significant survival advantage was noted in Mer(Tg) lymphocytes compared to wild-type lymphocytes after dexamethasone treatment. These data suggest that Mer plays a cooperative role in leukemogenesis and may be an effective target for biologically based leukemia/lymphoma therapy.
Insights
Mer tyrosine kinase (MerTK) plays a role in T-cell acute lymphoblastic leukemia. Overexpression of MerTK in mice led to leukemia development and increased survival after chemotherapy, suggesting it as a therapeutic target.
Area of Science:
- Molecular Biology
- Oncology
- Immunology
Background:
- Mer tyrosine kinase (MerTK) is crucial for platelet aggregation and macrophage functions.
- MerTK is typically absent in thymocytes and lymphocytes but ectopically expressed in some acute lymphoblastic leukemia (ALL) cases.
- This ectopic expression suggests a potential role for MerTK in leukemogenesis.
Purpose of the Study:
- To investigate the in vivo oncogenic potential of MerTK.
- To explore the role of MerTK in the development of leukemia.
- To assess MerTK as a potential therapeutic target for leukemia/lymphoma.
Main Methods:
- Creation of a transgenic mouse line (Mer(Tg)) expressing MerTK in hematopoietic cells under the Vav promoter.
- Analysis of MerTK expression and activation in lymphocytes and thymocytes of Mer(Tg) mice.
- Histopathological analysis, flow cytometry, and assessment of survival after dexamethasone treatment.
Main Results:
- Mer(Tg) mice exhibited ectopic MerTK expression and activation in lymphocytes and thymocytes.
- Over 55% of Mer(Tg) mice developed adenopathy, hepatosplenomegaly, and lymphoblasts, indicative of T-cell lymphoblastic leukemia/lymphoma.
- MerTK activation of Akt and ERK1/2 anti-apoptotic pathways was observed, and Mer(Tg) lymphocytes showed enhanced survival post-dexamethasone treatment.
Conclusions:
- MerTK plays a cooperative role in leukemogenesis.
- MerTK signaling contributes to leukemia development through anti-apoptotic pathways.
- MerTK represents a promising therapeutic target for leukemia and lymphoma.
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