Aberrant regulation of cell migration confers malignant properties of cancer cells and plays a critical role in leukemia progression and resistance. To date, very few molecules, including chemokine receptors have been implicated in T-cell lineage acute lymphoblastic leukemia (T-ALL) migration and CNS disease and/or relapse. The suppressors of the cytokine signaling (SOCS) family are known cytokine-inducible negative regulators of signal transduction, but their roles in regulating cell migration remain poorly understood. While it is clear that chemokine receptor signaling is important for T-ALL leukemogenesis and secondary organ infiltration, the roles of intrinsic signaling mediators of cell migration have been understudied. SOCS5 is a known regulator of JAK-STAT signaling and was shown to be involved in T-cell differentiation. We discovered downregulation of SOCS5 gene expression levels in a subset of high-risk T-ALL. Our preliminary findings provide strong evidence that silencing of SOCS5 expression enhances T-ALL cell migration and CNS infiltration, and induces upregulation of genes involved in cell migration. The goal of this study is to address how SOCS5 downregulation facilitates T-ALL migration leading to leukemic cell trafficking to the CNS. We hypothesize that SOCS5 downregulation promotes T-ALL migration leading to extramedullary tissue infiltration. Our rationale is that given functional similarities between hematopoietic stem cells and leukemic cells such as the ability to migrate, genes involved in T-cell development may contribute to enhancing aberrant signaling leading to increased migration and leukemia progression. Using T-ALL patient derived xenografts we will determine the roles of SOCS5 in the regulation of T-ALL cell migration.
In Aim 1, we will investigate the mechanism by which SOCS5 regulates expression of the CXCR3 chemokine receptor in migrating T-ALL cells. In our Aim 2, we propose to study the roles of SOCS5 downregulation in promoting T-ALL migration. Specifically, we will focus on the interaction between SOCS5 and LCK, a Src family kinase, in regulating T-ALL migration. Finally, in Aim 3, we will investigate how changes in SOCS5 expression affect T-ALL migration to medullary and extramedullary sites. The goal will be to establish the importance of SOCS5 downregulation in leukemia migration and infiltration of peripheral tissues, including the CNS. We expect to show the migratory potential of SOCS5 downregulation in T-ALL and establish the importance of negative regulators of signal transduction in T-ALL. Studying T-ALL migration can provide important information related to the mechanisms that cause leukemia survival and CNS infiltration, and will contribute to the development of novel treatment approaches. .
In this project we will investigate how SOCS5 regulates T-ALL cell migration and dissemination to secondary organs, including the Central Nervous System (CNS). We will conduct mechanistic studies unraveling the roles of SOCS5 and its targets such as CXCR3 or LCK in regulating leukemic cell migration. We will next determine the roles of SOCS5 in mediating T-ALL trafficking to the CNS in vivo. The goal will be to demonstrate the importance of SOCS5 in T-ALL progression and CNS infiltration.
