Abstract 2879: TYRO3 is a potential therapeutic target in pediatric acute myeloid leukemia
Authors: Smart Sherri K. , Rupji Manali , Dwivedi Bhakti , Kowalski Jeanne , DeRyckere Deborah , Graham Douglas K. 
Published: August 2019

BACKGROUND: While outcomes for children with acute myeloid leukemia have improved dramatically in recent years, a subset of patients continue to have poor prognosis with &lt;60% 5-year overall survival and the high intensity chemotherapy used to treat these patients is associated with significant short and long-term side effects. New less toxic and more effective treatments are needed. TYRO3, a member of the TAM (TYRO3, AXL, MERTK) family of receptor tyrosine kinases, is overexpressed in many types of cancer and functions to promote tumor cell survival and/or proliferation, metastasis, and resistance to chemotherapy. In addition, higher levels of TYRO3 expression are associated with decreased overall survival in patients with colorectal, hepatocellular or breast cancer. We hypothesize that TYRO3 plays a critical role in survival and proliferation of AML cells and may be a therapeutic target in pediatric AML.

METHODS: The TARGET database was utilized to determine expression of mRNAs encoding the TAM family kinases and their ligands, GAS6 and PROS1, in pediatric AML patient samples. Samples (n=145) were categorized into two groups with “high” expression greater than the median or “low” expression less than or equal to the median and overall survival was compared between the two groups using the log-rank test. Expression of TAM family kinases and ligands was determined in AML cell lines by immunoblot. Derivatives of the NB4 AML cell line with shRNA-mediated inhibition of TYRO3 were generated and the impact of TYRO3 inhibition on MERTK levels was determined by immunoblot.

RESULTS: High levels of TYRO3 or PROS1 mRNAs in patient samples were independently associated with decreased overall survival in children with AML (p&lt;0.001 and p= 0.042, respectively). Patients with leukemias that expressed higher levels of TYRO3 had a median survival of 870 days with only 40% of patients surviving for 10 years. In contrast, 70% of patients with leukemias that expressed lower levels of TYRO3 were long-term survivors. A hazard ratio of 2.60 (1.56-4.33 95% confidence interval, p&lt;0.001) was associated with high levels of TYRO3. Similarly, patients whose leukemias had higher levels of PROS1 expression had a median survival of 1229 days with 46% 10-year overall survival compared to 62% 10-year survival in patients whose tumors express low levels of PROS1. High levels of PROS1 were associated with a hazard ratio of 1.65 (1.01-2.68, p=0.044). TYRO3 protein was detected in all 9 AML cells lines tested; however, MERTK, GAS6, and PROS1 were differentially expressed. Inhibition of TYRO3 in NB4 cells using shRNA resulted in upregulation of MERTK.

CONCLUSIONS: TYRO3 was ubiquitously expressed in all AML cell lines tested and higher levels of TYRO3 and its ligand PROS1 were associated with significantly poorer prognosis in children with AML. These data suggest a role for TYRO3 in pediatric AML and implicate TYRO3 as a therapeutic target in this context.

Citation Format: Sherri K. Smart, Manali Rupji, Bhakti Dwivedi, Jeanne Kowalski, Deborah DeRyckere, Douglas K. Graham. TYRO3 is a potential therapeutic target in pediatric acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2879.