Knowledge of the mechanisms underlying the normal development of blood cells will lead to new understanding of the pathogenesis of acute leukemias. The long range goals are to further understanding of the mechanisms involved in leukemia, to develop new prognostic classifications based on molecular mechanisms, and then to develop more specific, less toxic therapies for leukemia (""""""""Transcription"""""""" therapies). The major hypotheses underlying this research program are that: (1) Acute-myelogenous leukemia (AML;) represents a block in hematopoietic cell differentiation; (2) Hematopoietic cell differentiation is largely determined by lineage specific transcription factors; (3) Therefore, :abnormalities in these transcription factors (mutation, decreased expression, post-translational modifications, abnormal cellular localization) are likely to play a major role in AML; (4) Detecting these abnormalities will lead to new classifications of AML and new prognostic indicators, much like those associated with specific chromosomal translocations; (S) These studies will lead to new strategies for treatment, either based on drug or gene therapy; and (6) These studies will form a paradigm for understanding and eventually developing specific therapies for other leukemias and cancers. Recent studies led to the identification of the transcription factor CCAAT Enhancer Binding Protein alpha (C/EBPa) as being absolutely critical for differentiation of normal myeloid blasts and has specific abnormalities in specific AML subtypes.
The specific aims are: (1) To demonstrate that mutant C/EBPa ; blocks differentiation in cell lines, primary bone marrow cells, and mouse models of human AML; (2) To further characterize the abnormalities in patients with AML and mutations in C/EBPa; and (3) To demonstrate that introduction of wild type C/EBPa can induce differentiation of leukemic cells as proof of aboutprinciple for development of future therapies. These studies will provide information concerning the pathogenesis and treatment of AML, as well as develop techniques applicable to other human cancers.
