Characterization of childhood acute lymphoblastic leukemia xenograft models for the preclinical evaluation of new therapies.
Continuous xenografts from 10 children with acute lymphoblastic leukemia (ALL) were established in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Relative to primary engrafted cells, negligible changes in growth rates and immunophenotype were observed at second and third passage. Analysis of clonal antigen receptor gene rearrangements in 2 xenografts from patients at diagnosis showed that the pattern of clonal variation observed following tertiary transplantation in mice exactly reflected that in bone marrow samples at the time of clinical relapse. Patients experienced diverse treatment outcomes, including 5 who died of disease (median, 13 months; range, 11-76 months, from date of diagnosis), and 5 who remain alive (median, 103 months; range, 56-131 months, following diagnosis). When stratified according to patient outcome, the in vivo sensitivity of xenografts to vincristine and dexamethasone, but not methotrexate, differed significantly (P =.028, P =.029, and P =.56, respectively). The in vitro sensitivity of xenografts to dexamethasone, but not vincristine, correlated significantly with in vivo responses and patient outcome. This study shows, for the first time, that the biologic and genetic characteristics, and patterns of chemosensitivity, of childhood ALL xenografts accurately reflect the clinical disease. As such, they provide powerful experimental models to prioritize new therapeutic strategies for future clinical trials.
Liem
Natalia L M
NL
Children's Cancer Institute Australia for Medical Research, Sydney, Australia.
Papa
Rachael A
RA
Milross
Christopher G
CG
Schmid
Michael A
MA
Tajbakhsh
Mayamin
M
Choi
Seoyeon
S
Ramirez
Carole D
CD
Rice
Alison M
AM
Haber
Michelle
M
Norris
Murray D
MD
MacKenzie
Karen L
KL
Lock
Richard B
RB
D000293:Adolescent; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D003907:Dexamethasone / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D015329:Gene Rearrangement, T-Lymphocyte; D005803:Genes, Immunoglobulin; D006801:Humans; D016130:Immunophenotyping; D008297:Male; D008727:Methotrexate / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology*; D014183:Transplantation, Heterologous; D016896:Treatment Outcome; D014750:Vincristine / Q000494:pharmacology / Q000627:therapeutic use
D000970:Antineoplastic Agents; D014750:Vincristine; D003907:Dexamethasone; D008727:Methotrexate