Bob Bast Translational Research Grant*
The proposed studies will address two major issues in treating two hematological cancers, myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML): limited new and effective treatments for the last 30 years; treatments that are optimal on a patient-specific basis. MDS and AML cells arise in the bone marrow from healthy hematopoietic stem cells. Accumulation of several mutations is involved in this process. In addition, other cells in the bone marrow can affect MDS or AML development or progression: stroma cells that give rise to bone, fat and other cell types. We have identified a new pathway of communication between MDS or AML cells and stromal cells. At least 35% of MDS and AML patients express high levels of JAGGED1 in their bone cells. Our studies in mice show that JAGGED overexpression leads to MDS/AML development. Conversely, blocking JAGGED1 in mice treats MDS and AML and prevents lethality. We generated human antibodies that block JAGGED1 activity and can be used in treating MDS and AML patients. Our purpose is to test efficacy of the most active human antibodies in all subtypes of MDS and AML using mouse models and cells from patients. We have developed a robust and simple screening test for identifying the patients who have the JAGGED1 pathway active using cells from their bone marrow. Our studies will benefit patients by screening and identifying the ones with pathway activity that can be treated with the antibody. This patient-specific approach should increase the precision and efficacy of treatment.
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