Extramedullary hematopoietic niches support the initiation and progression of myeloid malignancy in the murine spleen.

Although the spleen has been implicated in myeloid malignancy progression, the underlying mechanisms and microenvironmental remodeling remain poorly understood. Here, we investigated how splenic mesenchymal stromal/progenitor cells (MSPCs) expressing the transcription factor T-cell leukemia homeobox 1 (Tlx1) influence hematopoiesis and myeloid disease progression. We assessed their impact on hematopoietic stem/progenitor cells (HSPCs), leukemic cell recruitment, and disease progression. In vitro, Tlx1-overexpressing splenic stromal cells promoted the proliferation and survival of HSPCs. In vivo, using a murine acute myeloid leukemia (AML) model, AML progression induced extramedullary hematopoiesis (EMH) in the spleen through Tlx1 upregulation in MSPCs. This Tlx1-dependent remodeling facilitated leukemic cell recruitment and retention, whereas Tlx1 ablation in MSPCs significantly reduced leukemic cell accumulation in the spleen. Prolonged EMH in vivo was associated with the development of a myeloid malignancy. Collectively, these findings demonstrate that Tlx1-driven remodeling of the splenic microenvironment supports HSPC expansion and fosters conditions that promote myeloid malignancy development. Thus, targeting Tlx1-mediated alterations in the splenic niche may represent a therapeutic strategy for AML and related myeloid malignancies.