SERPIN SPI2A AS A NOVEL MODULATOR OF HEMATOPOIETIC PROGENITOR CELL FORMATION

Prime regulation over hematopoietic progenitor cell (HPC) production is exerted by hematopoietins (HP’s) and their Janus kinase-coupled receptors (HP-R’s). For HP/HP-R studies, one central challenge in determining specific effects involves the delineation of non-redundant signal transduction factors and their lineage restricted actions. Via loss-of-function (LOF) studies, we define roles for an HP-regulated Serpina3g/Spi2A intracellular serpin during granulomyelocytic, B-cell and HSC formation. In granulomyelocytic progenitors, GMCSF strongly induced Serpina3g expression with Stat5-dependency. Spi2A-KO led to 20-fold decreased CFU-GM formation, limited GMCSF-dependent granulocyte formation, and compromised neutrophil survival upon TNF-α exposure. In B-cell progenitors, Serpina3g was an IL7 target. Spi2A-KO elevated CFU-preB >6-fold, and altered B-cell formation in competitive BMT, and CpG challenge experiments. In HSCs, Serpina3g/Spi2A expression was also elevated. Spi2A-KO compromised LT-HSC proliferation (as well as LSK cell lysosomal integrity), and skewed LSK recovery post 5-FU. Spi2A therefore functions to modulate HP-regulated immune cell, and HSC formation post 5-FU challenge.