Clonally resolved single-cell multi-omics identifies routes of cellular differentiation in acute myeloid leukemia.
Sergi Beneyto-CalabuigAnne Kathrin MerbachJonas-Alexander KniffkaMagdalena AntesChelsea Szu-TuChristian RohdeAlexander WaclawiczekPatrick StelmachSarah GräßlePhilip PervanMaike JanssenJonathan J M LandryVladimir BenesAnna JauchMichaela BroughMarcus BauerBirgit BesenbeckJulia FeldenSebastian BäumerMichael HundemerTim SauerCaroline PabstClaudia WickenhauserLinus AngenendtChristoph SchliemannAndreas TrumppSimon HaasMichael SchererSimon RaffelCarsten Müller-TidowLars VeltenPublished in: Cell stem cell (2023)
Inter-patient variability and the similarity of healthy and leukemic stem cells (LSCs) have impeded the characterization of LSCs in acute myeloid leukemia (AML) and their differentiation landscape. Here, we introduce CloneTracer, a novel method that adds clonal resolution to single-cell RNA-seq datasets. Applied to samples from 19 AML patients, CloneTracer revealed routes of leukemic differentiation. Although residual healthy and preleukemic cells dominated the dormant stem cell compartment, active LSCs resembled their healthy counterpart and retained erythroid capacity. By contrast, downstream myeloid progenitors constituted a highly aberrant, disease-defining compartment: their gene expression and differentiation state affected both the chemotherapy response and leukemia's ability to differentiate into transcriptomically normal monocytes. Finally, we demonstrated the potential of CloneTracer to identify surface markers misregulated specifically in leukemic cells. Taken together, CloneTracer reveals a differentiation landscape that mimics its healthy counterpart and may determine biology and therapy response in AML.
Keyphrases
- single cell
- rna seq
- acute myeloid leukemia
- stem cells
- gene expression
- high throughput
- induced apoptosis
- allogeneic hematopoietic stem cell transplantation
- cell cycle arrest
- bone marrow
- magnetic resonance
- end stage renal disease
- cell therapy
- magnetic resonance imaging
- newly diagnosed
- ejection fraction
- oxidative stress
- prognostic factors
- climate change
- mesenchymal stem cells
- computed tomography
- radiation therapy
- immune response
- chronic kidney disease
- patient reported outcomes
- pi k akt
- peripheral blood
- locally advanced