Mutations in Patients with Myelodysplastic Syndromes Machado-Neto JA et al. observed the presence of the JAK2 V617F mutation in one patient with CMML after disease progression (case 1; Table 2). Figures 3 and 4 represent the RFLP analysis of the JAK2 V617 and FLT3-D835 mutations, respectively. DISCUSSION Acute leukemia results from a combination of muta- tions and changes in protein function that lead to an increase in proliferation and defects in differentiation and apoptosis.24 Although FLT3 and NPM1 mutations have been described with great frequency in cases of AML,25,26 these mutations were not detected in the MDS patients included in this study. As the presence of these mutations was investigated at the time of diagnosis, screening during disease progression could be interesting. Pinheiro and colleagues27 have reported the acquisition of the FLT3- ITD mutation in 2 of 50 MDS patients included in their study one year after diagnosis. These patients later progressed toward AML, suggesting that the ac- quisition of this mutation may be related to leukemic transformation. JAK2 mutations were not found in the MDS patients in this study at diagnosis. Interestingly, the JAK2 V617F mutation was identified in one CMML patient after disease progres- sion. Initially, this patient presented with fewer than 5% bone marrow blasts and lacked the JAK2 V617F mutation. We observed the presence of the JAK2 V617F mutation during disease progression, with increased white blood cell (WBC) counts and bone marrow blasts (at diagnosis: 9000 WBC/L, 3% bone marrow blasts; at disease progression: 60000 WBC/ L, 10% bone marrow blasts). JAK2 mutations occur in 10% of CMML cases and are associated with clinical and morpho- logical features.28 The JAK2 V617F mutation leads to constitutive activation of the JAK2/STAT3 pathway and aberrant signaling, resulting in growth factor independence, increased proliferation and differentiation failure.29 In light of the frequency of these events during MDS progression, our results suggest that the acquisition of JAK2 mutations may be involved in disease progression and should be investigated in more cases of MDS evolution. This finding is in agreement with other authors.30,31 A recent publication by Malcovati et al.31 reported 3 patients who evolved from RARS with normal platelet counts and wild-type JAK2 to RARS-T with JAK2 mutation at the time of transformation. Mutations in exons 9 and 20 of the PI3K gene are frequently described in cancer.4,5,13 However, we did not observe the presence of these mutations in the MDS patients included in this study. Constitutive activation of PI3K occurs in AML and high-risk MDS patients at diagnosis32-34, and mutations in exons 9 and 20 result in constitutive activation of this protein.5,14-17 The presence of PI3K mutations in AML5 justifies the evaluation of these muta- tions in a larger number of MDS patients, as they represent a possible factor involved in disease progression. The presence or absence of these mutations has prog- nostic value in AML,21 and therefore, the investigation of similar mutations in other myeloid diseases such as MDS could be interesting in the context of developing targeted therapies. The PI3K/Akt pathway has already been targeted in acute leukemia, and specific PI3K inhibitors, such as LY294002, have been tested in vitro.35 Other members of the PI3K signaling pathway have also been investigated as targets for leukemia treatment. Clinical studies with 798 CLINICS 2011;66(5):793-799 rapamycin analogues, which inhibitor mTOR, are currently in phase II AML trials, alone or in combination with other chemotherapeutics.36 Furthermore, FLT3 inhibitors have shown therapeutic activity in AML patients with FLT3 mutations,37 and selective JAK2 inhibitors have been tested in patients with JAK2 mutations.38 In summary, our study has shown that mutations in the JAK2, FLT3, NPM1 and PI3K genes are not common in patients with MDS at diagnosis and that JAK2 mutations may occur in MDS during disease progression. Further studies may be helpful to understand the involvement of genetic changes and the impact of these mutations in MDS progression and in different subgroups of patients with the disease. ACKNOWLEDGMENTS The authors would like to thank Raquel S. Foglio for English review. This work received financial support from the Conselho Nacional de Desenvolvimento Cient´ıfico e Tecnolo´gico (CNPq) and the Fundac¸a˜o de Amparo a` Pesquisa do Estado de Sa˜o Paulo (FAPESP). Contributions: Joa˜o Agostinho Machado-Neto contributed to the selection of patients, carried out all experiments and participated in the writing of the manuscript; Fabiola Traina contributed to the selection of patients, clinical follow-up of the patients, analysis of the results and the writing of the manuscript; Mariana Lazarini provided technical assistance with the experiments and participated in the writing of the manuscript; Paula de Melo Campos contributed to the selection of patients and clinical follow-up of the patients; Katia Borgia Barbosa Pagnano contributed to the clinical follow-up of the patients and with the techniques to detect the FLT3-ITD and NPM1 mutation; Irene Lorand-Metze was responsible for the morphological diagnosis of myelodysplastic syndrome in the patients included in this study; Fernando Ferreira Costa contributed to the analysis of the results; Sara T. Olalla Saad was the principal investigator. REFERENCES 1. List AF, Vardiman J, Issa JP, DeWitte TM. 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