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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA108922-03
Application #
7393273
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Mufson, R Allan
Project Start
2006-03-01
Project End
2008-05-31
Budget Start
2008-05-14
Budget End
2008-05-31
Support Year
3
Fiscal Year
2008
Total Cost
$258,530
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Pediatrics
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Mehta, Hrishikesh M; Malandra, Michael; Corey, Seth J (2015) G-CSF and GM-CSF in Neutropenia. J Immunol 195:1341-9
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
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; Corey, Seth J (2013) Drug repurposing in pediatrics and pediatric hematology oncology. Drug Discov Today 18:4-10

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