Beadex modulates hematopoiesis and innate immune defense against microbial infection in Drosophila melanogaster

Transcription factors play a crucial role during hematopoiesis with implications in leukemia. LIM-domain only proteins (LMO) are also found to be associated with chromosomal translocation in T-cell acute lymphoblastic leukemia and are highly expressed in acute myeloid leukemia, where they correlate with poor prognosis. However, their role in myeloid cell lineage specification and function is poorly understood. Using Drosophila melanogaster, which possesses a single LMO homolog, Beadex (dLMO), and a conserved myeloid-like immune system, we have shown its conserved role in plasmatocytes (equivalent to macrophages) development and innate immunity. Beadex is expressed in progenitor and differentiated plasmatocytes, and its loss reduced lymph gland size, mature plasmatocyte numbers and phagocytic efficiency. The phagocytes of Beadex mutant flies feature reduced filopodia length and lamellipodium area. Mechanistically, Beadex regulates actin remodelling by regulating the expression level of profilin (chickadee/chic), as chic overexpression rescued the defect in phagocytosis. Overexpression of Beadex in hemocytes increased fly susceptibility towards Salmonella enterica serovar Typhimurium infection and this mortality was due to an infection-induced pathology independent of bacterial burden. Bulk RNA sequencing of Beadex knockdown hemocytes revealed transcriptional changes in actin cytoskeleton regulatory genes, phagosome function and immune response pathways. In conclusion, our study identifies Beadex as a key transcriptional regulator impacting multiple aspects of myeloid cell function, ranging from hematopoiesis and cytoskeletal dynamics to host-level immune defense.