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.