Adverse stem cell clones within a single patient's tumor predict clinical 
outcome in AML patients

Zeller, Christina; Richter, Daniel; Jurinovic, Vindi; Valtierra-Gutierrez, Ilse A.; Jayavelu, Ashok Kumar; Mann, Matthias; Bagnoli, Johannes W.; Hellmann, Ines; Herold, Tobias; Enard, Wolfgang; Vick, Binje; Jeremias, Irmela

doi:10.1186/s13045-022-01232-4

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Adverse stem cell clones within a single patient's tumor predict clinical outcome in AML patients

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Jayavelu, Ashok Kumar
Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society;

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Mann, Matthias
Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society;

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Citation

Zeller, C., Richter, D., Jurinovic, V., Valtierra-Gutierrez, I. A., Jayavelu, A. K., Mann, M., et al. (2022). Adverse stem cell clones within a single patient's tumor predict clinical outcome in AML patients. Journal of Hematology & Oncology, 15: 25. doi:10.1186/s13045-022-01232-4.

Cite as: https://hdl.handle.net/21.11116/0000-000A-2ACB-3

Abstract

Acute myeloid leukemia (AML) patients suffer dismal prognosis upon treatment resistance. To study functional heterogeneity of resistance, we generated serially transplantable patient-derived xenograft (PDX) models from one patient with AML and twelve clones thereof, each derived from a single stem cell, as proven by genetic barcoding. Transcriptome and exome sequencing segregated clones according to their origin from relapse one or two. Undetectable for sequencing, multiplex fluorochrome-guided competitive in vivo treatment trials identified a subset of relapse two clones as uniquely resistant to cytarabine treatment. Transcriptional and proteomic profiles obtained from resistant PDX clones and refractory AML patients defined a 16-gene score that was predictive of clinical outcome in a large independent patient cohort. Thus, we identified novel genes related to cytarabine resistance and provide proof of concept that intra-tumor heterogeneity reflects inter-tumor heterogeneity in AML.