Different Roles of NPM1 and FLT3 Mutations in Myelodysplastic Syndromes
A Bains, R Luthra, LJ Medeiros, Z Zuo. Oklahoma University Health Sciences Center, Oklahoma City, OK; University of Texas MD Anderson Cancer Center, Houston, TX
Background: MDS constitutes a heterogeneous group of stem cell disorders characterized by ineffective hematopoiesis with an increased but variable risk of progression to AML. MDS are currently classified on the basis of clinical, morphologic, and cytogenetic data. A molecular understanding of MDS is needed for a more accurate classification, prognosis, and development of targeted therapy. Nucleophosmin (NPM1) and FLT3 are amongst the most commonly mutated genes in AML. The role of NPM1 and FLT3 mutations in MDS are less well studied.
Design: We identified 1316 patients with MDS or MDS/myeloproliferative neoplasm (MPN) who were tested for FLT3 mutation. A detailed analysis, including clinical history, bone marrow findings, cytogenetics and additional molecular tests, was performed on 160 of these patients who also had been tested for NPM1 mutation. Progression-free survival was estimated by the Kaplan-Meier method.
Results: Of 1316 patients with MDS tested, 26 (1.98%) were positive for FLT3 mutation. The distribution was: 15 of 875 (1.7%) de-novo MDS, 4 of 150 (2.7%) t-MDS, and 7 of 291 (2.4%) MDS/MPN. FLT3 mutation status did not correlate with cytogenetic results (normal or complex, p = 0.103 and 0.119, respectively). Seven of 160 (4.4%) patients had NPM1 mutations; 3 of 58 RAEB, 3 of 21 MDS/MPN, and 1 of 32 t-MDS. All had a normal karyotype, and four also carried FLT3 mutation (p = 0.002). No other tested mutations co-existed with NPM1. Patients with both NPM1 and FLT3 mutations progressed to AML (median duration of 12 months); however, so far none of the patients with mutated NPM1 alone progressed to AML. Progression to AML was associated with FLT3 mutation (p<0.001) and complex cytogenetics (p=0.019).
Conclusions: FLT3 mutations occur in approximately 2% of MDS cases and NPM1 mutations occur in about 4% of MDS cases; both at a much lower frequency than observed in AML. NPM1 positive cases of MDS share many similarities with NPM1 positive AML, including a normal karyotype and a tendency towards acquiring FLT3 mutation. Patients with NPM1 positive MDS have a low frequency of progression to AML, but MDS patients in whom both NPM1 and FLT3 mutations are present have a much higher risk of progression to AML. These results suggest that NPM1 mutation may not directly cause leukemogenesis, but it may predispose a progenitor/stem cell to malignant transformation as a result of an additional "hit" (FLT3 mutation or other unknown mechanism).
Tuesday, March 23, 2010 1:00 PM
Poster Session IV # 172, Tuesday Afternoon