title: Clonal selection in xenografted human T cell acute lymphoblastic leukemia recapitulates gain of malignancy at relapse.
abstract: Genomic studies in human acute lymphoblastic leukemia (ALL) have revealed clonal heterogeneity at diagnosis and clonal evolution at relapse. In this study, we used genome-wide profiling to compare human T cell ALL samples at the time of diagnosis and after engraftment (xenograft) into immunodeficient recipient mice. Compared with paired diagnosis samples, the xenograft leukemia often contained additional genomic lesions in established human oncogenes and/or tumor suppressor genes. Mimicking such genomic lesions by short hairpin RNA-mediated knockdown in diagnosis samples conferred a selective advantage in competitive engraftment experiments, demonstrating that additional lesions can be drivers of increased leukemia-initiating activity. In addition, the xenograft leukemias appeared to arise from minor subclones existing in the patient at diagnosis. Comparison of paired diagnosis and relapse samples showed that, with regard to genetic lesions, xenograft leukemias more frequently more closely resembled relapse samples than bulk diagnosis samples. Moreover, a cell cycle- and mitosis-associated gene expression signature was present in xenograft and relapse samples, and xenograft leukemia exhibited diminished sensitivity to drugs. Thus, the establishment of human leukemia in immunodeficient mice selects and expands a more aggressive malignancy, recapitulating the process of relapse in patients. These findings may contribute to the design of novel strategies to prevent or treat relapse.
authors.affiliation: Laboratoire de Recherche sur les Cellules Souches Hématopoïétiques et Leucémiques, Institut de Radiobiologie Cellulaire et Moléculaire, Commissariat à l'Energie Atomique et aux Energies Alternatives, 92265 Fontenay-aux-Roses, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Clappier
authors.forename: Bastien
authors.initials: B
authors.lastname: Gerby
authors.forename: François
authors.initials: F
authors.lastname: Sigaux
authors.forename: Marc
authors.initials: M
authors.lastname: Delord
authors.forename: Farah
authors.initials: F
authors.lastname: Touzri
authors.forename: Lucie
authors.initials: L
authors.lastname: Hernandez
authors.forename: Paola
authors.initials: P
authors.lastname: Ballerini
authors.forename: André
authors.initials: A
authors.lastname: Baruchel
authors.forename: Françoise
authors.initials: F
authors.lastname: Pflumio
authors.forename: Jean
authors.initials: J
authors.lastname: Soulier
mesh_terms: D000818:Animals; D002453:Cell Cycle; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D008938:Mitosis; D009368:Neoplasm Transplantation; D051059:PTEN Phosphohydrolase / Q000502:physiology; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D012008:Recurrence; D014183:Transplantation, Heterologous
chemical_list: D051059:PTEN Phosphohydrolase