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Blood, 1 June 2002, Vol. 99, No. 11, pp. 4100-4108
NEOPLASIA
The nonobese diabetic/severe combined immunodeficient
(NOD/SCID) mouse model of childhood acute lymphoblastic
leukemia reveals intrinsic differences in biologic characteristics
at diagnosis and relapse
Richard B. Lock,
Natalia Liem,
Monica L. Farnsworth,
Christopher G. Milross,
Chengyuan Xue,
Mayamin Tajbakhsh,
Michelle Haber,
Murray D. Norris,
Glenn M. Marshall, and
Alison
M. Rice
From the Children's Cancer Institute Australia for
Medical Research; School of Paediatrics, University of New South Wales;
Department of Radiation Oncology, Prince of Wales Hospital; and Sydney
Children's Hospital, Sydney, Australia.
Acute lymphoblastic leukemia cells from 19 children,
including 7 who remain in first complete remission (CR1), were
engrafted into nonobese diabetic/severe combined immunodeficient
(NOD/SCID) mice. High-level infiltration of bone marrow, spleen, and
liver was observed, with variable infiltration of other organs. The immunophenotypes of xenografts were essentially unaltered compared with
the original patient sample. In addition, sequencing of the entire p53
coding region revealed no mutations in 14 of 14 xenografts (10 from
patients at diagnosis and 4 at relapse). Cells harvested from the
spleens of engrafted mice readily transferred the leukemia to secondary
and tertiary recipients. To correlate biologic characteristics of
xenografts with clinical and prognostic features of the patients, the
rates at which individual leukemia samples engrafted in NOD/SCID mice
were analyzed. Differences in biologic correlates were encountered depending on stage of disease: a direct correlation was observed between the rate of engraftment and length of CR1 for samples harvested
at relapse (r = 0.96; P = .002), but not
diagnosis (r = 0.38; P = .40). In contrast,
the in vivo responses of 6 xenografts to vincristine showed a direct
correlation (r = 0.96; P = .002) between
the length of CR1 and the rate at which the leukemia cell population recovered following vincristine treatment, regardless of
whether the xenografts were derived from patients at diagnosis or
relapse. This study supports previous findings that the NOD/SCID model
of childhood ALL provides an accurate representation of the human
disease and indicates that it may be of value to predict relapse and
design alternative treatment strategies in a patient-specific manner.
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