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Blood, Vol. 94 No. 2 (July 15), 1999:
pp. 733-740
Microsatellite Instability and p53 Mutations Are Associated With
Abnormal Expression of the MSH2 Gene in Adult Acute Leukemia
Y.-M. Zhu,
E.P. Das-Gupta, and
N.H. Russell
From the Division of Haematology, Department of Clinical Laboratory
Sciences, the University of Nottingham, UK.
Microsatellite instability (MSI) and p53 mutations have been
reported to occur in a significant proportion of patients with therapy-related acute myeloid leukemia (AML). MSH2 is one
of the genes involved in DNA mismatch repair to maintain fidelity of genomic replication, and defects of MSH2 are directly involved in MSI
in hereditary nonpolyposis colorectal tumors and other human tumors. We
have examined the expression of MSH2 protein by Western blotting in 43 adult leukemia samples, including 42 AML and 1 acute lymphoblastic
leukemia (ALL) using the antibody MSH2 (Ab-1) (Calbiochem,
La Jolla, CA). Abnormal expression of MSH2 protein was
found in 14 of 43 (32.6%) cases; a control antibody to actin was
always positive. Of the 14 patients that had abnormal expression of
MSH2, 2 had therapy-related acute leukemia and 9 were elderly patients
(>60 years of age). Expression of MSH2 mRNA was further examined by
reverse transcriptase-polymerase chain reaction (RT-PCR).
Deletion of MSH2 mRNA was found in 1 of 14 cases with deficient MSH2
protein expression. This group of patients was also screened for loss
of heterozygosity (LOH) at the MSH2 locus using a panel 4 microsatellite markers (D2S367, D2S288, D2S391, and D2S2294). LOH was
found in 5 of 11 cases examined. There was no evidence of LOH in 14 patients with normal MSH2 expression who were examined using the same
markers. Functional evidence for defective DNA mismatch repair in
leukemic cells lacking MSH2 as manifest by MSI was found in 7 of 11 cases studied. Mutations of the p53 gene in these 43 samples were also
investigated by direct sequencing of full-length p53 cDNA. Mutations of
p53 were found in 6 of 43 cases, including 5 of the 14 (35.7%) cases
that did not express MSH2 protein. In contrast, mutation of p53 was only found in 1 of 29 (3.4%) cases with normal MSH2 protein expression ( 2 = 5.720, P < .02). These results suggest
that abnormalities of DNA mismatch repair due to defective MSH2
expression could play a key role in leukemogenesis, in particular in
AML arising in elderly patients or secondary to previous chemotherapy.
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