SUMMARY Transcription factors play essential roles in establishing the correct gene expression patterns unique to each cell type. These finely controlled patterns can fall apart if a mutation resides within a critical factor. In the hematopoietic system, this can lead to anemia, dysplasia, or leukemia of varying morbidities. Overcoming transcription factor deficits is highly challenging, especially if the mutation is solely in one of the two alleles and if complete removal of the protein’s expression is not an option. Experiments in this proposal addresses the problem in the context of the congenital dyserythropoietic anemia (CDA) caused by a single missense mutation in one allele of the KLF1(EKLF) transcription factor. Technological development of state-of-the-art approaches to selectively target and degrade the mutant variant will be designed and tested. Specifically, the method relies on the cellular introduction of degradative modules (degrons) coupled to targeting motifs based on KLF1/DNA interactions, the details of which are to be based on published and proposed methods of identifying parameters of binding selectivity. These studies, summarized in two Aims that cover (1) in vitro tests and (2) in vivo (cell culture) approaches, will have a transformative effect well beyond the immediate case, as they provide an innovative and distinctive blueprint for the direct removal of problematic proteins in other hematologic and renal diseases caused by monoallelic missense mutations in transcription factor DNA binding domains.