Acute myelogenous leukemia is a disease in which the accumulation of primitive nonfunctional precursor cells results in the death of 80% of patients due to bleeding and infection. Although allogeneic bone marrow transplantation is curative, only 25% of AML patients are eligible for this therapy, and only half of these survive long term. Another 10-20% of patients are cured by combination chemotherapy. In order to develop new directions of therapy for AML, we are proposing to use cloned growth regulatory molecules to specifically sensitize the leukemia cells to phase specific agents. We will also use these growth factors to characterize the defects present in the subsets of AML which are associated with specific chromosomal translocations. We will use this information to identify targets for therapy in AML. The therapy will be based on growth factor therapy, combination chemotherapy, and bone marrow transplantation. These treatment programs will be linked to laboratory assays which will provide short-term molecular endpoints for the evaluation of response and minimal residual disease. We will classify patients with respect to a proliferative response or a differentiation induction response to a hematopoietic growth factor. We will compare in vitro with in vivo responses. We will compare proliferative responses in vitro and in vivo to growth factor induced changes in growth factor receptors, cytoplasmic signal transduction molecules, growth factor synthesis, intranuclear growth regulatory proteins (P53 and RB), early response gene expression, and killing of leukemic cells by phase specific agents and before and after exposure to myeloid growth factors. We will use PCR assays specific for each of the chromosomally defined subsets of AML to define response to therapy, response to growth factors and minimal residual disease. We will use this information to build sequential therapeutic programs which integrate chemotherapy with growth factors, used singly and in combinations. In this way, we hope to be able to develop therapy which is targeted to the molecular and biological defects in these diseases, which is less toxic to normal tissues and provides more durable remissions in all subsets of AML.
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