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.

1
Lamandin
 
C
Sagot
 
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Roumier
 
C
et al
Are PU.1 mutations frequent genetic events in acute myeloid leukemia (AML)? [letter].
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2
Mueller
 
BU
Pabst
 
T
Osato
 
M
et al
Heterozygous PU.1 mutations are associated with acute myeloid leukemia.
Blood.
100
2002
998
1007
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.
27
2001
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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.
99
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1332
1340
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.
100
2002
2717
2723
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.
7
2001
444
451
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.
18
1998
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333
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.
101
2003
270
277
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