Cancers · 2026
Single-Cell Multi-Omics Identifies Measurable Residual Disease Targets Among Myelodysplasia- and Clonal Hematopoiesis-Related Genes in Acute Myeloid Leukemia.
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Sørensen Emma Frasez, Arvé Caroline, Gronlund Jonas K, Melsvik Dorte, Pold Johanne Amalie, Knudsen Michael, Thorsen Kasper, Aggerholm Anni, Ommen Hans Beier
Аннотация
BACKGROUND: In acute myeloid leukemia (AML), the most sensitive measurable residual disease (MRD) methods are single-gene approaches, but these are applicable only in ~60% of AML cases.
METHODS: We applied multi-omics single-cell analysis on diagnostic and first remission samples to identify leukemia-specific molecular markers for subsequent MRD monitoring in six AML patients lacking AML-defining variants.
RESULTS: Five selection criteria were defined to identify suitable MRD markers. Markers of primordial leukemic clones were identified by combining data from single-cell sequencing and immunophenotyping. Specific markers suitable for use in MRD follow-up were identified in 6/6 patients, in some cases in myelodysplasia-related genes and clonal hematopoiesis-related genes usually not recommended for use in MRD determinations. Patient-specific ddPCR (limits of detection: 0.06-0.0011%) or EC-NGS assays correlated with therapeutic responses: 0/4 markers displayed molecular relapses in three non-relapsing patients, contrary to 4/4 markers of three relapsing patients. Of these, 3/4 and 1/4 markers detected molecular relapses earlier than or simultaneous with conventional methods, respectively (-115 to -338 days).
CONCLUSIONS: Our results demonstrate that single-cell subclonal mapping at diagnosis and during first remission enables selection of reliable MRD targets for personalized disease surveillance in patients lacking conventional MRD markers.
METHODS: We applied multi-omics single-cell analysis on diagnostic and first remission samples to identify leukemia-specific molecular markers for subsequent MRD monitoring in six AML patients lacking AML-defining variants.
RESULTS: Five selection criteria were defined to identify suitable MRD markers. Markers of primordial leukemic clones were identified by combining data from single-cell sequencing and immunophenotyping. Specific markers suitable for use in MRD follow-up were identified in 6/6 patients, in some cases in myelodysplasia-related genes and clonal hematopoiesis-related genes usually not recommended for use in MRD determinations. Patient-specific ddPCR (limits of detection: 0.06-0.0011%) or EC-NGS assays correlated with therapeutic responses: 0/4 markers displayed molecular relapses in three non-relapsing patients, contrary to 4/4 markers of three relapsing patients. Of these, 3/4 and 1/4 markers detected molecular relapses earlier than or simultaneous with conventional methods, respectively (-115 to -338 days).
CONCLUSIONS: Our results demonstrate that single-cell subclonal mapping at diagnosis and during first remission enables selection of reliable MRD targets for personalized disease surveillance in patients lacking conventional MRD markers.