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CORRESPONDENCE Recently, Mueller et al1 found PU.1 mutations
in 7% of the 126 cases of acute myeloid leukemia (AML) they analyzed.
DNA binding and transactivation of the M-CSF receptor promoter, a direct PU.1 target gene, were deficient in the 7 mutants that affected
the DNA-binding domain of the PU.1. Those mutations also decreased the
ability of PU.1 to synergize with proteins such as AML1 or c-Jun,
possibly contributing to the differentiation block found in AML. We
looked for study analysis of PU.1 gene mutations in 77 cases of primary
AML (excluding therapy-related AML and AML following MDS): 30 M0, 10 M1, 11 M2, 11 M4, 13 M5, 1 M6 AML, and 1 M7 AML, according to FAB
classification.2 In all blood and marrow samples analyzed,
more than 80% of blasts were present. Detection of PU.1 gene
mutations was made on DNA by single-strand conformation polymorphism
(SSCP) analysis3 and direct sequencing of the 5 exons corresponding to the entire coding region of the PU.1
gene. The size of the polymerase chain reaction (PCR) products was 190 bp to 440 bp (Table
1). Except for a polymorphism in intron 3 (G>A transversion), no abnormal SSCP profile and no variation of sequence of the PU.1 gene was observed
in the 77 de novo AML cases studied.
Our results are in contrast to those of Mueller et al1 but in agreement with results of Vegesna et al,4 who found no mutation in 60 AML patients tested. There are no clear explanations for these discrepancies. Vegesna et al4 only used SSCP analysis for screening of mutations, but we also used, like Mueller et al, direct sequencing. We and Vegesna et al4 used intronic primers and performed analyses on DNA, whereas Mueller et al1 performed direct sequencing on cDNA of the PU.1 gene. As 2 of the 9 mutations reported by Mueller et al1 corresponded to large deletions, probably not detectable by techniques using DNA, such mutations could have been overlooked in our study. Mutations reported by Mueller et al1 predominantly occurred in undifferentiated AML (M0 AML) or in AML of the monocytic lineage (M4 and M5 AML), but we included a large proportion of those cases in our study and none of them were mutated. Other hypotheses for those discrepancies include ethnic differences, as patients studied by Mueller et al1 were, to a large extent, part of the Japanese cohort studied by Osato et al5 for AML1 mutations. Finally, we and Vegesna et al4 included only cases of primary AML (excluding therapy-related MDS and AML following MDS), and 3 of the 9 mutated patients reported by Mueller et al1 corresponded to AML after MDS. Vegesna et al4 found no PU.1 mutations in 60 MDS patients, but PU.1 mutations could possibly occur during the progression of MDS to AML in some patients. In conclusion, we were unable to identify a significant number of PU.1 mutations in our patient population with AML, although their occurrence in some patients during the progression of MDS to AML cannot be excluded.
Charlotte Lamandin, Christophe Sagot, Christophe Roumier, Pascale Lepelley, Stéphane De
Botton, Alain Cosson, Pierre Fenaux, and Claude Preudhomme Supported by the Centre Hospitalier Universitaire of Lille (PHRC 1997), the Ligue Nationale contre le cancer (Comité du Nord et de l'Aisne), and the fondation de France (Comité Leucémie) References
1.
Mueller BU, Pabst T, Osato M, et al.
Heterozygous PU.1 mutations are associated with acute myeloid leukemia.
Blood.
2002;100:998-1007 2. Benett J, Catovsky D, Daniel MT, et al. Proposals for the classification of acute leukemias, a report of the French-American-British Cooperative Group. Br J Haematol. 1976;33:454-458. 3. Orita M, Suzuki Y, Sekiya T, Hayashi K. Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. Genomics. 1989;5:874-879[CrossRef][Medline] [Order article via Infotrieve].
4.
Vegesna V, Takeuchi S, Hofmann WK, et al.
C/EBP
5.
Osato M, Asou N, Abdalla E, et al.
Biallelic and heterozygous point mutations in the runt domain of the AML1/PEBP2   CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
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| Copyright © 2002 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
, C/EBP
, PU.1, AML1 genes: mutational analysis in 381 samples of hematopoietic and solid malignancies.
Leukemia Res.
2002;26:451-457
B gene associated with myeloblastic leukemias.
Blood.
1999;93:1817-1824
