title: Xenografts of highly resistant leukemia recapitulate the clonal composition of the leukemogenic compartment.
abstract: Clonal evolution of the leukemogenic compartment may contribute to alter the therapeutic response in acute lymphoblastic leukemia (ALL). Using xenotransplantation of primary leukemia cells, we evaluated the phenotypic and genetic composition of de novo resistant very high risk precursor B-cell ALL, a subgroup defined by the persistence of minimal residual disease despite intensive chemotherapy. Analysis of copy number alterations (CNAs) showed that the xenografted leukemia, even when reconstituted from 100 cells, remained highly related to the diagnostic sample, with minor changes in CNAs, mostly deletions, emerging in most cases in the first passage into mice. At the single-cell level, the pattern of monoallelic and biallelic deletions of the CDKN2A locus revealed distinct leukemia subpopulations, which were reproducibly tracked in xenografts. In most very high risk ALL cases, the predominant diagnostic clones were reconstituted in xenografts, as shown by multiplex polymerase chain reaction analysis of immunoglobulin and T-cell receptor loci. In other cases, the pattern in CNAs and immunoglobulin and T-cell receptor rearrangement was less concordant in xenografts, suggesting the outgrowth of subclones. These results unequivocally demonstrate the existence of clonally closely related but distinct subsets of leukemia initiating cells in ALL, which has important implications for drug development and preclinical disease modeling.
authors.affiliation: Division of Oncology and Children's Research Center, University Children's Hospital, University of Zurich, Zurich, Switzerland.
authors.forename: Maike
authors.initials: M
authors.lastname: Schmitz
authors.forename: Petra
authors.initials: P
authors.lastname: Breithaupt
authors.forename: Nastassja
authors.initials: N
authors.lastname: Scheidegger
authors.forename: Gunnar
authors.initials: G
authors.lastname: Cario
authors.forename: Laura
authors.initials: L
authors.lastname: Bonapace
authors.forename: Barbara
authors.initials: B
authors.lastname: Meissner
authors.forename: Paulina
authors.initials: P
authors.lastname: Mirkowska
authors.forename: Joelle
authors.initials: J
authors.lastname: Tchinda
authors.forename: Felix K
authors.initials: FK
authors.lastname: Niggli
authors.forename: Martin
authors.initials: M
authors.lastname: Stanulla
authors.forename: Martin
authors.initials: M
authors.lastname: Schrappe
authors.forename: Andre
authors.initials: A
authors.lastname: Schrauder
authors.forename: Beat C
authors.initials: BC
authors.lastname: Bornhauser
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bourquin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002999:Clone Cells; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D017353:Gene Deletion; D018628:Gene Dosage; D015321:Gene Rearrangement; D015329:Gene Rearrangement, T-Lymphocyte; D005803:Genes, Immunoglobulin; D006801:Humans; D051379:Mice; D018365:Neoplasm, Residual; D010641:Phenotype; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D019941:Cyclin-Dependent Kinase Inhibitor p16