Rapid recovery and functional resilience of bone marrow function post B-cell acute lymphoblastic leukemia

Leukemia often causes changes in the bone marrow (BM) microenvironment, but the extent to which this is associated with long term impairment of functional hematopoiesis remains unclear. Using a mouse model of B-cell acute lymphoblastic leukemia (B-ALL), we dissected how leukemia reshapes the BM microenvironment and redirects hematopoiesis to the spleen. We found that leukemic mice accumulate a markedly expanded pool of functional, long-term multilineage hematopoietic stem cells in the spleen, arising alongside a transient disruption of the CXCL12 gradient. Single-cell transcriptomics revealed changes in cytokine profiles, niche cell composition, and gene expression in the leukemic BM, while the changes in the spleen were less pronounced. Despite the niche distortion in the BM, selective ablation of leukemic cells led to rapid hematopoietic regeneration, with BM reconstitution detectable within just 4 days. Consistent with these findings, we observed an increased frequency of lineage restricted progenitor cells in B-ALL patients already 15 days after initiation of treatment. These findings uncover an unexpected robustness of BM niche function and suggest that B-ALL driven microenvironmental alterations do not prevent swift recovery of hematopoiesis following removal of malignant cells.