Abstract 3749: MER receptor tyrosine kinase overexpression potentiates survival signal in chronic lymphocytic leukemia cells
Authors: Mendez Mariana T. , Mahmud Hasan , Vesely Sara K. , Holter-Chakrabarty Jennifer , Ghosh Asish K. 
Published: September 2020

Chronic lymphocytic leukemia (CLL) is the most common form of adult B-cell leukemia in the United States. It is predominantly characterized by the accumulation of CD19+/CD5+/CD23+ monoclonal B-cells in peripheral blood, bone marrow and lymphoid tissues.

BCR signaling pathway has emerged as a key driver for the expansion of neoplastic B-cell clones and pathogenesis in several B-cell malignancies including CLL. Stimulation of BCR induces activation of a cascade of downstream signal mediators including Bruton's tyrosine kinase (BTK), PI3K/AKT and ERK1/2. While the use of BCR-targeted agents, ibrutinib (BTK-inhibitor) or idelalisib (PI3Kδ-inhibitor), has been shown to be effective in relapsed/refractory CLL patients, the responses are limited to partial remissions. Therefore, insights into drugs with unique mechanism(s) of action that are nontoxic to the bone marrow/immune system and feasible in the older patient population (average age: 65 - 70 years) are urgently needed. To achieve such a goal it is critical to identify other targets that are constitutively active and may crosstalk with the BCR signal or other receptor tyrosine kinases (RTKs). MER RTK of the TAM (Tyro3, AXL, MER) family offers such an alternative approach.

Previously, we detected that CLL B-cells express highly active AXL that acts as a docking site of multiple kinases/lipase including LYN, SYK/ZAP70, PI3K and PLCγ2 that, when subject to specific inhibition induces apoptosis. Most recently, we found that CLL B-cells from 50 - 60% of previously untreated CLL patients (n=30) also overexpressed MER at variable levels while, normal B-cells from health subjects did not show any such expression. Interestingly, MER in CLL B-cells remains constitutively phosphorylated (active). In addition, we also detected overexpression of its ligand, growth arrest specific gene 6 (Gas6) in CLL B-cells as compared to normal B-cells. Of note, leukemic B-cells from the Eμ-TCL1 transgenic mice which recapitulate aggressive human CLL also showed overexpression of MER. To this end, we found that exogenous addition of recombinant Gas6 to primary CLL B-cell culture or MEC1 (a CLL cell line) cells activated MER in a time-dependent manner. Interestingly, we also detected co-activation of BTK of the BCR pathway, following MER activation in CLL cells while, in vitro stimulation of BCR did not activate MER. Together, these findings suggest that MER activation may regulate the BCR signal in CLL B-cells in order to potentiate the survival signal.

In conclusion, we detected overexpression of constitutively activated MER in CLL B-cells from some CLL patients which may represent high-risk CLL clones for clinical progression. Importantly, activation of MER may positively regulate the BCR signal inducing increased survival and apoptotic resistance of the leukemic B-cells to BCR-targeted agents. Further studies are in progress to elucidate the impact of targeting MER in CLL B-cell survival and resistance to therapy.

Citation Format: Mariana T. Mendez, Hasan Mahmud, Sara K. Vesely, Jennifer Holter-Chakrabarty, Asish K. Ghosh. MER receptor tyrosine kinase overexpression potentiates survival signal in chronic lymphocytic leukemia cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3749.