Distinct immunologic vs progenitor landscapes in myeloid leukemia recurrence: Adaptive immune persistence in pediatrics vs niche exhaustion in adults.

Abstract

10021 Background: Recurrent myeloid leukemia remains a therapeutic challenge with distinct clinical trajectories across age groups. While our parallel study identified a "universal adipogenic shift" in the marrow stroma common to all ages, the specific cellular drivers distinguishing pediatric from adult relapse remain undefined. We hypothesized that against this shared stromal background, the mechanism of recurrence diverges: the pediatric marrow mounts an adaptive immune response, whereas the aging adult marrow suffers from hematopoietic reservoir depletion. Methods: We analyzed the tumor microenvironment (TME) of 2,378 myeloid leukemia samples (2,007 primary, 371 recurrent) using xCell transcriptomic deconvolution. The cohort was stratified into Pediatric (< 18y, n = 2,071) and Adult ( ≥ 18y, n = 307) subgroups to control for ontogenic baselines. We compared differential expression rankings between primary and recurrent states using Mann-Whitney U tests with Bonferroni correction (Padj) to identify age-specific dominance in TME remodeling. Results: Comparative analysis revealed divergent TME landscapes between age groups. In pediatrics, recurrence was characterized by an "Immune-Adaptive" program; CD4+ Memory T-cells were the dominant signature (rank 4, p < 10⁻²⁷), alongside significant increases in Preadipocytes ( p < 10⁻⁴⁹) and pro-B cells. Conversely, adult recurrence exhibited "Niche Exhaustion," primarily losing hematopoietic progenitors (CMP/GMP, p <10⁻⁷) and mesenchymal stem cells (MSC, p < 10⁻⁹). While CD4+ Memory T-cells increased in adults, the signal was less prominent (rank 18, p < 10⁻⁵). Both groups shared significant vascular collapse (Pericyte loss, p < 10⁻⁷), identifying it as a universal hallmark of relapse. Conclusions: Myeloid leukemia recurrence is driven by age-distinct microenvironmental remodeling. Pediatric relapse is defined by immune adaptation and adipogenesis, while adult relapse is characterized by progenitor and niche exhaustion. Vascular collapse represents a universal therapeutic target. These findings suggest that immunotherapy and niche-directed treatments must be tailored to the patient’s age-specific TME landscape to improve outcomes. Top age-specific trends in recurrent vs. primary myeloid leukemias. Cohort Cell Type Direction Mean Diff (Rec - Pri) Padj Pediatric (<18y) Pericytes Primary- High -0.085 P < 0.05 Preadipocytes Recurrence- High +0.064 P < 0.05 MSC Primary- High -0.099 P < 0.05 CD4+ Memory T-cells Recurrence- High +0.849 P < 0.05 pro-B cells Recurrence- High +0.301 P < 0.05 Adult (≥18y) MSC Primary- High -0.165 P < 0.05 Pericytes Primary- High -0.078 P < 0.05 CMP Primary- High -0.526 P < 0.05 Smooth muscle Primary- High -0.094 P < 0.05 GMP Primary- High -0.765 P < 0.05 CD4+ Memory T-cells* Recurrence- High +1.184 P < 0.05 *Manually added row for comparison purposes.