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Zeller, C. ; Richter, D.* ; Jurinovic, V. ; Valtierra-Gutierrez, I.A.* ; Jayavelu, A.K.* ; Mann, M.* ; Bagnoli, J.W.* ; Hellmann, I.* ; Herold, T. ; Enard, W.* ; Vick, B. ; Jeremias, I.

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

J. Hematol. Oncol. 15:25 (2022)

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Genetic Barcoding ; Heterogeneity ; In Vivo Treatment ; Single Cell ; Therapy Resistance ; Xenograft Mouse Model; Acute Myeloid-leukemia

e-ISSN 1756-8722

Journal Journal of Hematology & Oncology

Quellenangaben Volume: 15, Issue: 1, Article Number: 25

Publisher BioMed Central

Publishing Place London

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)

Grants German Research Foundation (DFG/Gottfried Wilhelm Leibniz Prize)
Max Planck Society for the Advancement of Science
Helmholtz Zentrum Munchen
Dr. Helmut Legerlotz Stiftung
Bettina Brau Stiftung
DFG
German Cancer Aid
European Research Council
German Research Foundation (DFG) Collaborative Research Center 1243 "Genetic and Epigenetic Evolution of Hematopoietic Neoplasms"