Single-cell RNA-seq reveals developmental plasticity with coexisting oncogenic states and immune evasion programs in ETP-ALL.
Praveen AnandAmy Guillaumet-AdkinsValeriya DimitrovaHuiyoung YunYotam DrierNoori SotudehAnna J RogersMadhu M OusephMonica NairSayalee PotdarRandi IsenhartJake A KloeberTushara VijaykumarLeili NiuTiffaney VincentGuangwu GuoJulia FredeMarian H HarrisAndrew E PlaceLewis B SilvermanDavid Trent TeacheyAndrew A LaneDaniel J DeAngeloJon C AsterBradley E BernsteinJens G LohrBirgit KnoechelPublished in: Blood (2021)
Lineage plasticity and stemness have been invoked as causes of therapy resistance in cancer, because these flexible states allow cancer cells to dedifferentiate and alter their dependencies. We investigated such resistance mechanisms in relapsed/refractory early T-cell progenitor acute lymphoblastic leukemia (ETP-ALL) carrying activating NOTCH1 mutations via full-length single-cell RNA sequencing (scRNA-seq) of malignant and microenvironmental cells. We identified 2 highly distinct stem-like states that critically differed with regard to cell cycle and oncogenic signaling. Fast-cycling stem-like leukemia cells demonstrated Notch activation and were effectively eliminated in patients by Notch inhibition, whereas slow-cycling stem-like cells were Notch independent and rather relied on PI3K signaling, likely explaining the poor efficacy of Notch inhibition in this disease. Remarkably, we found that both stem-like states could differentiate into a more mature leukemia state with prominent immunomodulatory functions, including high expression of the LGALS9 checkpoint molecule. These cells promoted an immunosuppressive leukemia ecosystem with clonal accumulation of dysfunctional CD8+ T cells that expressed HAVCR2, the cognate receptor for LGALS9. Our study identified complex interactions between signaling programs, cellular plasticity, and immune programs that characterize ETP-ALL, illustrating the multidimensionality of tumor heterogeneity. In this scenario, combination therapies targeting diverse oncogenic states and the immune ecosystem seem most promising to successfully eliminate tumor cells that escape treatment through coexisting transcriptional programs.
Keyphrases
- single cell
- rna seq
- cell cycle
- cell proliferation
- induced apoptosis
- acute lymphoblastic leukemia
- acute myeloid leukemia
- public health
- cell cycle arrest
- high throughput
- transcription factor
- end stage renal disease
- bone marrow
- stem cells
- signaling pathway
- climate change
- ejection fraction
- chronic kidney disease
- high intensity
- oxidative stress
- mass spectrometry
- multiple myeloma
- human health
- binding protein
- genome wide
- pi k akt
- prognostic factors
- newly diagnosed
- epithelial mesenchymal transition
- gene expression
- allogeneic hematopoietic stem cell transplantation
- heat shock
- dna methylation
- squamous cell carcinoma
- peritoneal dialysis
- risk assessment
- papillary thyroid
- mesenchymal stem cells
- cancer stem cells