Identification of cells of leukemic stem cell origin with non-canonical regenerative properties

Despite most acute myeloid leukemia (AML) patients entering remission following chemotherapy, outcomes remain poor due to surviving leukemic cells that contribute to relapse. The nature of these enduring cells is poorly understood. Here, through temporal single-cell transcriptomic characterization of AML hierarchical regeneration in response to chemotherapy, we reveal a cell population: AML regeneration enriched cells (RECs). RECs are defined by CD74/CD68 expression, and although derived from leukemic stem cells (LSCs), are devoid of stem/progenitor capacity. Based on REC in situ proximity to CD34-expressing cells identified using spatial transcriptomics on AML patient bone marrow samples, RECs demonstrate the ability to augment or reduce leukemic regeneration in vivo based on transfusion or depletion, respectively. Furthermore, RECs are prognostic for patient survival as well as predictive of treatment failure in AML cohorts. Our study reveals RECs as a previously unknown functional catalyst of LSC-driven regeneration contributing to the non-canonical framework of AML regeneration. [Display omitted] •Single-cell transcriptomics of AML PDXs during chemo-induced regrowth reveals RECs•Patient-derived RECs are devoid of stem cell capacity but predict patient outcome•Spatial transcriptomics of AML BM biopsies reveal proximity of RECs to primitive cells•Functional analyses reveal RECs non-canonically catalyze leukemic regeneration Hollands et al. discover a subset of acute myeloid leukemia cells termed regeneration enriched cells (RECs). RECs do not have stemness properties, but functionally catalyze leukemic regeneration in vivo post chemotherapy. This causal role provides evidence for non-canonical leukemic regrowth as a potential biomarker or therapeutic target in preventing relapse.