ABSTRACT: Background: Concurrent acute myeloid leukemia (AML) and a Waldenström macroglobulinemia (WM)-related compartment within the same bone marrow are uncommon. Conventional diagnostics can establish coexistence but incompletely resolve the cellular architecture and shared immune context of collision marrows. Methods: We performed single-cell RNA sequencing on the diagnostic bone marrow aspirate from a 67-year-old man with AML showing myelomonocytic features and a flow-validated WM-related B/plasma-cell compartment. Transcriptomic findings were integrated with marrow flow cytometry, serum studies, orthogonal MYD88 L265P testing, and longitudinal clinical assessment. Descriptive analyses included unsupervised clustering, lineage annotation, copy-number inference, AML state scoring, T/NK subclustering, and exploratory cell-cell communication inference. Results: Single-cell profiling resolved AML-related myeloid, WM-related B/plasma-cell, T/NK, monocyte, and erythroid/megakaryocytic compartments. Copy-number inference localized the dominant CNV-bearing population to AML-associated regions, with AML cells distributed across immature/progenitor-like, granulocytic-primed, and inflammatory/myelomonocytic-like states. The WM-related compartment comprised co-existing B-cell-like and plasma-cell-like states, with limited CNV resolution by transcriptome-based inference. Flow cytometry, monoclonal IgM, and MYD88 L265P supported a clonal WM-related process. Immune profiling identified an effector-dominant T/NK milieu with a discrete KLRC1-high cytotoxic subset and a T/NK-centered inhibitory signaling landscape. After azacitidine plus venetoclax, both compartments initially decreased, but later showed dissociated kinetics with AML re-expansion, persistent low-level WM-related marrow involvement, and sustained serologic abnormality. Conclusions: Integrated single-cell and orthogonal profiling showed that this collision marrow comprised an AML-dominant CNV-bearing leukemic compartment and a clinically anchored WM-related lymphoplasmacytic compartment, with dissociated kinetics under the same regimen. These findings illustrate the exploratory value of compartment-aware single-cell analysis in composite marrow malignancies.
