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In many hematopoietic malignancies such as lymphomas and leukemias, aberrant differentiation is the major feature of the malignant phenotype that often results from a single genetic alteration and provides a site-specific target for therapy. Therefore, targeting of protein-protein interactions that have been identified as mediators of transcriptional repression that blocks normal hematopoietic differentiation holds great promise for therapeutic applications. An example is GATA-1, a critical erythroid transcription factor that is capable of suppressing the myeloid phenotype by down-regulating PU.1 in a dose-dependent manner. PU.1 is the most crucial transcription factor known to be required for myeloid differentiation of hematopoietic stem/progenitor cells. Its reduced expression correlates with a bad prognosis and immature phentoype in acute myeloid leukemia (AML). GATA-1 downregulates PU.1 by interacting though its C-terminal zinc finger region with the β3/β4 region of PU.1 and displacing its coactivator c-Jun. We hypothesize that disruption of PU.1-GATA-1 interaction by mutating the β3/β4 region of PU.1 may prevent its GATA-1-mediated repression, which in turn will upregulate PU.1 expression and hence myelopoiesis. Our analysis of the PU.1 mutants, Lys240Arg and Tyr244Ala, revealed that they exhibit an increase in myelopoiesis in vitro. Thus our data have implications for the prospect of targeting PU.1-GATA-1 interaction for therapeutic intervention. N at u