Background and objectives: The precise relationship between myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) is unclear and the role of molecular mutations in leukemic transformation in MDS is controversial. The aim of this study was to clarify the relationship between AML and MDS by comparing the frequency of molecular mutations in the two conditions.
Design and methods: We compared the frequency of FLT3-length mutations (FLT3-LM), FLT3-TKD, MLL-partial tandem duplications (MLL-PTD), NRAS, and KITD816 in 381 patients with MDS refractory anemia with excess blasts [RAEB] n=49; with ringed sideroblasts [RARS] n=310; chronic monomyelocytic leukemia [CMML] n=22) and in 4130 patients with AML (de novo: n=3139; secondary AML [s-AML] following MDS: n=397; therapy-related [t-AML]: n=233; relapsed: n=361).
Results: All mutations were more frequent in s-AML than in MDS and all but the FLT3-TKD were more frequent in RAEB than in RA/RARS. The higher incidences in s-AML were significant for FLT3-TKD (p=0.032), MLL-PTD (p=0.034), and FLT3-LM (RA/RARS: 0/45; RAEB: 8/293; 2.7%; s-AML: 45/389; 11.6%; p<0.0001). The incidence of NRAS-mutations increased from 17/272 (6.3%) in MDS to 41/343 in s-AML (12.0%) and that of KITD816-mutations from 2/290 (0.7%) to 5/341 (1.5%) (p=n.s.). FLT3-LM-acquisition occurred in 3/22 cases (13.6%) during MDS transformation; NRAS-acquisition occurred in 1/24 (4.2%). FLT3-LM and MLL-PTD were more frequent in AML relapse than in de novo AML or s-AML (p<0.0001).
Interpretation and conclusions: The increase of molecular mutations from low- to high-risk MDS, to s-AML, and to relapsed AML emphasizes the value of these mutations as markers of progressing disease. Finally, we found a low rate of 5q- in the molecularly mutated cases in MDS which might explain the stability of this subtype.