Hematopoietic Stem Cell Transcription Factor PU.1 with Mutated β3/β4 Domain Selectively Elicits Myeloid Differentiation
Year: 2010
Type: preprint
Abstract: In many hematopoietic malignancies such as lymphomas & leukemias, aberrant differentiation is the major feature of 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 cells or progenitor cells. Its reduced expression correlates with a bad prognosis and immature phenotype 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.
Source: Nature Precedings
Authors: Pallavi Gupta, Gurudutta Gangenahalli, Daman Saluja, Yogesh Verma, Jyoti Zack, Vimal Singh, Neeraj Satija, Rajendra Tripathi
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7095952107