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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)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Genetic Barcoding ; Heterogeneity ; In Vivo Treatment ; Single Cell ; Therapy Resistance ; Xenograft Mouse Model; Acute Myeloid-leukemia
e-ISSN 1756-8722
Zeitschrift Journal of Hematology & Oncology
Quellenangaben Band: 15, Heft: 1, Seiten: , Artikelnummer: 25 Supplement: ,
Verlag BioMed Central
Verlagsort London
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)
Förderungen 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"