Single-cell dissection of a collision marrow with coexisting acute myeloid leukemia and a Waldenström-related...

The concurrent presence of acute myeloid leukemia (AML) and a Waldenström macroglobulinemia (WM)-related compartment within the same bone marrow is uncommon. Conventional diagnostics can establish coexistence but cannot completely resolve the cellular architecture and shared immune context of collision marrows.

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-cell/natural killer (T/NK) subclustering, and exploratory cell-cell communication inference.

Single-cell profiling resolved AML-related myeloid, WM-related B/plasma-cell, T/NK, monocyte, and erythroid/megakaryocytic compartments. Copy-number variation (CNV) 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 coexisting 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.

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.