3220 – PERTURBED POST-TRANSCRIPTIONAL REGULATION VIA STAU1 LOSS CONTRIBUTES TO ERYTHROID DIFFERENTIATION DEFECTS IN DEL(20Q) DISORDERED HEMATOPOIESIS

Del(20q) is a recurrent cytogenetic abnormality observed across a broad spectrum of myeloid disorders. Although del(20q) has long been associated with ineffective erythro- and megakaryopoiesis, its underlying molecular mechanisms remain unclear. We identified Staufen1 (STAU1), a highly multifunctional double-stranded RNA-binding protein with enriched expression in multipotent and erythroid-primed populations, to be among genes disrupted on 20q. We therefore hypothesize that STAU1 plays an essential role in controlling hematopoietic stem and progenitor cell (HSPC) differentiation, and that its haploinsufficiency contributes to del(20q) disordered hematopoiesis. To characterize the functional consequences of STAU1 loss in human HSPCs, we performed shRNA-knockdown of STAU1 in CD34+ cord blood (CB). Strikingly, we found that ∼50% STAU1-knockdown resulted in complete ablation of erythroid colony-forming capacity, stalled both erythroid and megakaryocytic differentiation in suspension culture, and significantly reduced GlyA+ engraftment in NSG-W41 xenografts without affecting myeloid/lymphoid output or stem cell frequency. Through integrating transcriptomics, proteomics, and the novel RNA–protein interaction profiling method Surveying Targets by APOBEC Mediated Profiling (STAMP), we uncovered stabilizing interactions between STAU1 and lysosome-associated transcripts in CD34+ CB. Independent knockdown of these targets regenerated the shSTAU1 erythroid differentiation defect, suggesting a model wherein STAU1 promotes lysosome function and its centrally important role in iron trafficking and erythropoiesis. Altogether, we identify STAU1 as a critical regulator of human erythropoiesis and uncover, for the first time, post-transcriptional dysregulation contributing to del(20q) pathogenesis.