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Blood, 1 March 2003, Vol. 101, No. 5, pp. 2074-2074
CORRESPONDENCE
To the editor:
Heterozygous PU.1 mutations are associated with acute myeloid
leukemia
We appreciate the information from Lamandin et
al,1 in which his group was unable to identify
PU.1 mutations in their patient samples with acute myeloid leukemia
(AML). As a result, we have reviewed all of our own primary
sequencing data and confirmed the results that were reported in our
article.2 As reported in the article, sequencing results
from samples containing mutations were independently repeated 3 to 6 times, including repetitions of the polymerase chain reaction
(PCR) and sequencing with alternative primers. In 3 patients
we had available both cDNA and genomic DNA at diagnosis, and the
mutation was detectable from both sources. Since the publication, we
have detected an additional PU.1 mutation in a patient with t(8;21)
AML. We agree that our use of screening by direct DNA sequencing of
both cDNA and genomic samples, as well as ethnic differences in the
patient populations, could account for some of the differences between
our results. We respectfully believe that PU.1 mutations do occur in some
patients with primary AML, as has been found with another myeloid transcription factor, C/EBP alpha.3-5 Additional studies
analyzing larger numbers of patients from different ethnic groups may
be needed to assess the true frequency of such mutations. At the same
time, as has been described in the case of C/EBP alpha, other mechanisms affecting PU.1, such as down-regulation6 and/or inhibition of activity,7,8 may also implicate loss of PU.1 function in other cases of AML that do not harbor mutations.
Beatrice U. Mueller, Thomas Pabst, Motomi Osato, Norio Asou, Lisa M. Johansen, Mark D. Minden, Gerhard Behre, Wolfgang Hiddemann, Yoshiaki Ito, and Daniel G. Tenen
Correspondence: Daniel G. Tenen, Harvard
Institutes of Medicine, Rm 954, 77 Avenue Louis Pasteur, Boston, MA
02115; e-mail: dtenen{at}caregroup.harvard.edu
References
1.
Lamandin C, Sagot C, Roumier C, et al.
Are PU.1 mutations frequent genetic events in acute myeloid leukemia (AML)? [letter].
Blood.
2002;100:4680[Free Full Text].
2.
Mueller BU, Pabst T, Osato M, et al.
Heterozygous PU.1 mutations are associated with acute myeloid leukemia.
Blood.
2002;100:998-1007[Abstract/Free Full Text].
3.
Pabst T, Mueller BU, Zhang P, et al.
Dominant negative mutations of CEBPA, encoding CCAAT/Enhancer Binding Protein alpha (C/EBP alpha), in acute myeloid leukemia.
Nat Genet.
2001;27:263-270[CrossRef][Medline]
[Order article via Infotrieve].
4.
Gombart AF, Hofmann WK, Kawano S, et al.
Mutations in the gene encoding the transcription factor CCAAT/enhancer binding protein alpha in myelodysplastic syndromes and acute myeloid leukemias.
Blood.
2002;99:1332-1340[Abstract/Free Full Text].
5.
Preudhomme C, Sagot C, Boissel N, et al.
Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia: a study from the Acute Leukemia French Association (ALFA).
Blood.
2002;100:2717-2723[Abstract/Free Full Text].
6.
Pabst T, Mueller BU, Harakawa N, Zhang DE, Tenen DG.
AML1ETO downregulates the granulocytic differentiation factor C/EBP alpha in t(8;21) myeloid leukemia.
Nat Med.
2001;7:444-451[CrossRef][Medline]
[Order article via Infotrieve].
7.
Westendorf JJ, Yamamoto CM, Lenny N, Downing JR, Selsted ME, Hiebert SW.
The t(8:21) fusion product, AML1ETO, associates with C/EBP alpha, inhibits C/EBP alpha dependent transcription, and blocks granulocytic differentiation.
Mol Cell Biol.
1998;18:322-333[Abstract/Free Full Text].
8.
Vangala RK, Heiss-Neumann MS, Rangatia JS, et al.
The myeloid master regulator transcription factor PU.1 is inactivated by AML1-ETO in t(8;21) myeloid leukemia.
Blood.
2003;101:270-277[Abstract/Free Full Text].
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