Universal adipogenic and immunologic remodeling in the recurrent myeloid leukemia microenvironment of recurrent versus primary myeloid leukemias: An age-stratified analysis.

Abstract

6596 Background: Disease recurrence is the primary cause of mortality in myeloid leukemias. While molecular studies suggest leukemic cells actively reprogram marrow stroma to create a self-reinforcing niche, natural age-related adiposity confounds whether this remodeling is disease-intrinsic or a byproduct of aging. We sought to validate the "disease-intrinsic" hypothesis by delineating the landscape of recurrent disease across a large-scale transcriptomic cohort, rigorously distinguishing leukemic reprogramming from physiologic aging. Methods: We analyzed 2,378 myeloid leukemia samples (2,007 primary, 371 recurrent) from NCI genomic datasets via xCell computational deconvolution. To control for ontogenic marrow changes, the cohort was stratified into Pediatric (<18 years, n = 2,071) and Adult (≥ 18 years, n = 307) subgroups. Demographic analysis confirmed balanced gender and race distributions (p > 0.05); age disparity was explicitly corrected via the stratified design. Differences in tumor microenvironment (TME) composition were assessed using Mann-Whitney U tests, with Bonferroni-corrected p-values (Padj) calculated to ensure statistical rigor. Results: Recurrent tumors exhibited a profound, convergent stromal remodeling independent of age. The 'adipogenic shift' via Preadipocyte enrichment was observed in both Pediatric (P < 10⁻⁴⁸) and Adult (P < 10⁻⁴) recurrences. Conversely, vascular collapse was universal, characterized by a significant reduction of Pericytes in both Pediatric (P < 10⁻⁷²) and Adult (P < 10⁻⁸) cohorts. Immunologically, CD4+ Memory T cells were consistently enriched in both Pediatric (P < 10⁻²⁶) and Adult (P < 10⁻⁴) groups, suggesting a convergent mechanism of adaptive immune persistence in the relapsed setting. Conclusions: We demonstrate that recurrent myeloid leukemia drives a convergent microenvironmental evolution characterized by vascular collapse, pathologic adiposity, and immune persistence, independent of patient age. These findings corroborate that stromal remodeling is a dominant, disease-intrinsic program actively driven by leukemic cells rather than a passive reflection of aging. Validating this "adipogenic shift" as a universal resistance mechanism identifies the adipogenic and vascular niches as priority targets for therapeutic intervention across the spectrum of myeloid malignancies. Differential enrichment of microenvironmental populations in recurrent vs. primary myeloid neoplasms. Cohort Cell Type Direction Mean Diff (Rec - Pri) Padj Pediatric (<18y) Preadipocytes Recurrence- High +0.064 p < 0.05 Pericytes Primary- High -0.085 p < 0.05 CD4+ Memory T-cells Recurrence- High +0.849 p < 0.05 Adult (≥18y) Preadipocytes Recurrence- High +0.056 p < 0.05 Pericytes Primary- High -0.078 p < 0.05 CD4+ Memory T-cells Recurrence- High +1.184 p < 0.05