Although cure rates for acute lymphoblastic leukemia (ALL) have improved dramatically in the last thirty years, new therapeutic strategies are still needed for patients that show poor treatment response and those that relapse. Mer receptor tyrosine kinase is aberrantly expressed in lymphocytes of a subset of patients with B cell and T cell ALL, and a mouse model that overexpresses Mer in lymphocytes develops T cell lymphoblastic leukemia. We hypothesize that Mer is a contributing factor, in combination with other oncogenes, for the onset of leukemogenesis and is an attractive target for the development of biologic inhibitors for the treatment of leukemia. In the first aim, we will use the bone marrow transplant assay to identify the oncogenic pathways that cooperate with Mer to induce leukemogenesis. Bone marrow cells derived from the Mer transgenic, wild-type or Mer knockout mice will be transfected with oncogenic constructs and subsequently transplanted into sublethally irradiated mice. The kinetics of leukemia onset will be monitored in relation to Mer expression to identify the oncogenes that cooperate with Mer expression. These experiments will help suggest pathways that can be inhibited in combination with Mer to provide a multi-target therapeutic strategy. In the second and third aims, we propose to develop a clinically relevant model of Mer inhibition therapy in leukemia. Using inducible shRNA-mediated downregulation of Mer in pediatric leukemia cell lines, we will be able to mimic biologically targeted Mer inhibition in the cell lines once they have engrafted in a NOD/SCID mouse model. This approach will elucidate the role of Mer in leukemia maintenance and determine the efficacy of Mer inhibition in the treatment of leukemia, both as a monotherapy and in conjunction with standard leukemia chemotherapy agents.
Cancer is the leading cause of disease-related deaths in children, with acute lymphoblastic leukemia (ALL) being the most common form of childhood cancer. Mer receptor tyrosine kinase is abnormally expressed in subsets of patients with B cell and T cell ALL, and a mouse model with constitutive Mer expression in white blood cells develops T cell leukemia. We propose that Mer is an important factor in the development of leukemia and a relevant target for the development of new therapeutic agents for the treatment of childhood ALL.
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|Brandão, Luis; Migdall-Wilson, Justine; Eisenman, Kristen et al. (2011) TAM receptors in leukemia: expression, signaling, and therapeutic implications. Crit Rev Oncog 16:47-63|
|Linger, Rachel M A; DeRyckere, Deborah; Brandão, Luis et al. (2009) Mer receptor tyrosine kinase is a novel therapeutic target in pediatric B-cell acute lymphoblastic leukemia. Blood 114:2678-87|