Myelodysplastic Syndromes (MDS) are a disorder, increasing in frequency, for which there is poor understanding of its pathophysiology and no curative therapy short of an allogeneic stem cell transplant. Since most patients are elderly, new therapeutic strategies are desperately needed. MDS evolves from dysregulated clonal hematopoiesis to acute myeloid leukemia (AML). In early MDS, there is accelerated apoptosis of blood cells in a hypercellular bone marrow. In late MDS, apoptosis is deficient and a block in differentiation occurs. Our laboratory has been studying signaling pathways in cells stimulated by Granulocyte Colony-Stimulating Factor (G-CSF). Abnormal G-CSF Receptor signaling is found in several forms of pediatric and adult MDS: 1) children with severe congenital neutropenia have a 10,000-fold increase risk of developing MDS/AML - almost all of whom express a truncated G-CSF Receptor; 2) expression of the differentiation-defective G-CSF Receptor isoform is elevated in AML, MDS, and monosomy 7 patients; 3) a functional polymorphism affecting the distal, domain of the G-CSF Receptor occurs in MDS patients. Therefore, we hypothesize that disordered myelopoiesis due to dysfunctional G-CSF Receptor signaling underlies some cases of MDS and that targeted therapy may successfully delay or prevent leukemic transformation. We have identified the Src kinase Lyn as a major effector of G-CSF Receptor signaling. Chiefly limited to blood cells, Lyn provides a feasible drug target. To address these hypotheses, we propose the following specific aims: 1) Characterize the Lyn-dependent growth controlling pathways driven by the distal domain of the G-CSF Receptor and determine their presence in primary MDS cells; 2) Characterize the signaling changes due to increased expression of Class IV G-CSF Receptor and its presence in primary MDS cells; and 3) Test the effect of Lyn targeted therapy in mouse model and cell lines. These studies will provide rationale for a phase II study using Src inhibitors for subsets of MDS patients. ? ?
| Mehta, Hrishikesh M; Malandra, Michael; Corey, Seth J (2015) G-CSF and GM-CSF in Neutropenia. J Immunol 195:1341-9 |
| Mehta, Hrishikesh M; Glaubach, Taly; Corey, Seth Joel (2014) Systems approach to phagocyte production and activation: neutrophils and monocytes. Adv Exp Med Biol 844:99-113 |
| Mehta, H M; Futami, M; Glaubach, T et al. (2014) Alternatively spliced, truncated GCSF receptor promotes leukemogenic properties and sensitivity to JAK inhibition. Leukemia 28:1041-51 |
| Blatt, Julie; Farag, Sherif; Corey, Seth J et al. (2014) Expanding the scope of drug repurposing in pediatrics: the Children's Pharmacy Collaborative. Drug Discov Today 19:1696-1698 |
| Glaubach, Taly; Minella, Alex C; Corey, Seth J (2014) Cellular stress pathways in pediatric bone marrow failure syndromes: many roads lead to neutropenia. Pediatr Res 75:189-95 |
| Glaubach, Taly; Robinson, Lisa J; Corey, Seth J (2014) Pediatric myelodysplastic syndromes: they do exist! J Pediatr Hematol Oncol 36:1-7 |
| Schafernak, Kristian T; Corey, Seth J (2014) Histiocytic clearance of neoplastic cells in acute promyelocytic leukemia. Blood 124:3020 |
| Mehta, Hrishikesh M; Corey, Seth J (2014) Linking stress granulopoiesis to protein synthesis through GADD34. Immunol Cell Biol 92:102-4 |
| Corey, Seth Joel; Kimmel, Marek; Leonard, Joshua N (2014) Systems hematology: an introduction. Adv Exp Med Biol 844:3-10 |
| Blatt, Julie; Corey, Seth J (2013) Drug repurposing in pediatrics and pediatric hematology oncology. Drug Discov Today 18:4-10 |
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