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Wilms' Tumor (WT1) Gene Mutations Occur Mainly in Acute
Myeloid Leukemia and May Confer Drug Resistance
L. King-Underwood and
K. Pritchard-Jones
From the Section of Paediatric Oncology, Institute of Cancer
Research, Belmont, Sutton, Surrey, UK.
In a previous study of acute leukemia, we have shown that
WT1 gene mutations occur in both myeloid and biphenotypic
subtypes, where they are associated with refractoriness to standard
induction chemotherapy. We have now extended this study to a total of
67 cases (34 acute myeloid leukemia [AML], 23 acute lymphoblastic leukemia [ALL], 10 acute undifferentiated leukemia
[AUL]/biphenotypic) and find that WT1 mutations
occur in 14% of AML and 20% of biphenotypic leukemia, but are rare in
ALL (one case). In contrast to the findings in Wilms' tumor, where
mutations in the WT1 gene usually behave according to
Knudson's two hit model for tumor suppressor genes, seven of eight
leukemia-associated WT1 mutations are heterozygous, implying a
dominant or dominant-negative mode of action in hematopoietic cells. In
AML, the presence of a WT1 mutation is associated with failure
to achieve complete remission and a lower survival rate. These data (1)
confirm that WT1 mutations underlie a similar proportion of
cases of AML to that seen in Wilms' tumors and (2) show for the first
time that WT1 mutations can contribute to leukemogenesis of
lymphoid as well as myeloid origin, suggesting that its normal role in
hematopoiesis lies at a very early progenitor stage. The relationship
of WT1 mutation to chemoresistance merits further investigation.
Blood, Vol. 91 No. 8 (April 15), 1998:
pp. 2961-2968
© 1998 by The American Society of Hematology.
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