Regulation and function of nuclear envelope proteins in myelopoiesis and leukemia

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DESCRIPTION (provided by applicant): Neutrophils and monocytes/macrophages are essential components of the innate immune system and function to eradicate bacterial and certain fungal infections. These cells share both developmental and functional features, but they also have unique nuclear features that distinguish them from other white blood cells: neutrophils have a lobulated nucleus and monocytes bear an irregular, kidney-shaped nucleus. How these altered nuclear structures form is unclear, but deficient expression of an inner nuclear envelope protein called the lamin B receptor (LBR) causes neutrophil hypolobulation characteristic of Pelger-Hukt anomaly, and macrophages express certain nuclear envelope proteins and intermediate filament proteins called A-type lamins that are essentially lacking in other hematopoietic cells. The molecular mechanisms that create irregular nuclear features of these myeloid cells are of clinical interest because neutrophils with abnormal nuclear structure are associated with myelodysplasias that often progress to myeloid leukemias, and aberrant expression of nuclear envelope proteins has been identified in both leukemias and lymphomas. The long-term objective of this proposal is to identify the transcriptional mechanisms that drive the unique expression patterns of nuclear envelope proteins in developing myeloid cells, and to identify the roles that these proteins play in regulating myeloid cell development and their acquisition of critical functions. To achieve these objectives, the specific aims are to i) define the functions of a transcription factor, GA- binding protein (GABP), in regulating the expression of LBR, ii) identify additional targets of GABP that play important roles in orchestrating changes in nuclear structure of developing neutrophils and macrophages, and iii) manipulate the expression of NE proteins and A-type lamins in myeloid progenitors and identify effects on myeloid cell proliferation, differentiation and function. To achieve these aims, interactions of mouse Gabp with the Lbr gene promoter will be characterized, and novel mouse myeloid progenitors that lack Gabp function will be generated and analyzed for neutrophil and macrophage differentiation. Vectors that provide for, or inhibit, nuclear envelope or A-type lamin protein expression will be introduced into myeloid progenitors, and effects on differentiation, morphologic maturation and functional responses will be assessed. These studies will provide an understanding of the mechanisms that control different nuclear envelope protein expression patterns in developing myeloid cells, identify the importance of these expression patterns to myeloid differentiation, and help to explain why hematopoietic malignancies often result in aberrant nuclear structures in myeloid cells. PUBLIC HEALTH RELEVANCE: The objective of this proposal is to identify the molecular mechanisms that cause unique nuclear structural features to form in two blood cells that are critical to innate immunity, neutrophils and macrophages, and define the roles that nuclear envelope proteins play in orchestrating their nuclear features. These studies are relevant to public health because they will provide a better understanding of why aberrant nuclear structure and disrupted expression of nuclear envelope proteins are associated with hematologic malignancies, including life-threatening myelodysplasias and myelogenous leukemias.