Single-cell spatial mapping reveals dynamic bone marrow microarchitectural alterations and enhances clinical diagnostics in MDS

Assessment of myelodysplastic neoplasms (MDS) relies on histomorphology and blast enumeration, metrics that incompletely capture marrow architecture and disease state during therapy. We developed a quantitative spatial profiling platform to define a tissue-level biomarker of MDS using whole-slide multiplex immunofluorescence imaging and single-cell phenotyping. Diagnostic biopsies (n=36), longitudinal treatment samples (n=29), precursor states (n=13), and normal controls (n=21) were analyzed, comprising >5 million spatially resolved cells. MDS marrow exhibited coordinated, genotype-imprinted microarchitectural remodeling, including altered progenitor composition and spatial patterning, disrupted erythroid topology, and displacement of hematopoietic stem and progenitor cells from perivascular niches. We evaluated 82 cellular and spatial features and designed a weighted composite metric, the MDS Microarchitectural Perturbation Score (MDS-MAPS), derived from diagnostic samples and locked before longitudinal analysis. In leave-one-patient-out cross-validation, MDS-MAPS discriminated remission from active disease more accurately than blast percentage (AUC 0.883 vs 0.660; average precision 0.567 vs 0.250) and outperformed mutation burden–based metrics in distinguishing low-blast MDS from CCUS (AUC 0.815; average precision 0.890). Mixed-effects modeling showed MAPS decreased in remission independent of blast burden, with architectural normalization at remission and re-emergence of spatial perturbations at relapse. These findings define quantitative marrow architecture as a dynamic, clinically deployable tissue-state biomarker that complements molecular and blast-based assessment in MDS. One Sentence Summary A spatially resolved bone marrow tissue-state biomarker improves assessment of disease activity and remission beyond blast counts in myelodysplastic neoplasms. Competing Interest Statement The authors have declared no competing interest. Footnotes

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