Adverse stem cell clones within a single patient's tumor predict clinical outcome in AML patients
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Adverse stem cell clones within a single patient's tumor predict clinical outcome in AML patients. / Zeller, Christina; Richter, Daniel; Jurinovic, Vindi; Valtierra-Gutiérrez, Ilse A; Jayavelu, Ashok Kumar; Mann, Matthias; Bagnoli, Johannes W; Hellmann, Ines; Herold, Tobias; Enard, Wolfgang; Vick, Binje; Jeremias, Irmela.
In: Journal of Hematology & Oncology, Vol. 15, No. 1, 12.03.2022, p. 25.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Adverse stem cell clones within a single patient's tumor predict clinical outcome in AML patients
AU - Zeller, Christina
AU - Richter, Daniel
AU - Jurinovic, Vindi
AU - Valtierra-Gutiérrez, Ilse A
AU - Jayavelu, Ashok Kumar
AU - Mann, Matthias
AU - Bagnoli, Johannes W
AU - Hellmann, Ines
AU - Herold, Tobias
AU - Enard, Wolfgang
AU - Vick, Binje
AU - Jeremias, Irmela
N1 - © 2022. The Author(s).
PY - 2022/3/12
Y1 - 2022/3/12
N2 - 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.
AB - 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.
KW - Clone Cells
KW - Cytarabine/therapeutic use
KW - Drug Resistance, Neoplasm/genetics
KW - Humans
KW - Leukemia, Myeloid, Acute/drug therapy
KW - Proteomics
KW - Recurrence
KW - Stem Cells/pathology
U2 - 10.1186/s13045-022-01232-4
DO - 10.1186/s13045-022-01232-4
M3 - Journal article
C2 - 35279202
VL - 15
SP - 25
JO - Journal of Hematology & Oncology
JF - Journal of Hematology & Oncology
SN - 1756-8722
IS - 1
ER -
ID: 303113164