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Blood, Vol. 95 No. 3 (February 1), 2000:
pp. 738-743
PLENARY PAPER
Large deletions at the t(9;22) breakpoint are common and may
identify a poor-prognosis subgroup of patients with chronic myeloid
leukemia
P. B. Sinclair,
E. P. Nacheva,
M. Leversha,
N. Telford,
J. Chang,
A. Reid,
A. Bench,
K. Champion,
B. Huntly, and
A. R. Green
From the University of Cambridge, Department of Hematology, MRC
Centre, Cambridge, United Kingdom (UK); the Department of Hematology,
Addenbrooke's Hospital, Cambridge, UK; the Sanger Centre, Wellcome
Trust Genome Campus, Hinxton, Cambridge, UK; and the Department of
Hematology and Cytogenetics, Christie's Hospital, Manchester, UK.
The hallmark of chronic myeloid leukemia (CML) is the
BCR-ABL fusion gene, which is usually formed as a result of the
t(9;22) translocation. Patients with CML show considerable
heterogeneity both in their presenting clinical features and in the
time taken for evolution to blast crisis. In this study, metaphase
fluorescence in situ hybridization showed that a substantial minority
of patients with CML had large deletions adjacent to the translocation
breakpoint on the derivative 9 chromosome, on the additional partner
chromosome in variant translocations, or on both. The
deletions spanned up to several megabases, had variable
breakpoints, and could be detected by microsatellite polymerase
chain reaction in unfractionated bone marrow and purified peripheral
blood granulocytes. The deletions were likely to occur early and
possibly at the time of the Philadelphia (Ph) chromosome translocation:
deletions were detected at diagnosis in 11 patients, were found
in all Ph-positive metaphases, and were more prevalent in
patients with variant Ph chromosomes. Kaplan-Meier analysis showed a
median survival time of 36 months in patients with a deletion; patients
without a detectable deletion survived > 90 months. The survival-time
difference was significant on log-rank analysis (P = .006).
Multivariate analysis demonstrated that the prognostic importance of
deletion status was independent of age, sex, percentage of peripheral
blood blasts, and platelet count. Our data therefore suggest that an
apparently simple, balanced translocation may result not only in the
generation of a dominantly acting fusion oncogene but also in the loss
of one or more genes that influence disease progression.
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