TY - JOUR
T1 - TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients
AU - Bejar, Rafael
AU - Lord, Allegra
AU - Stevenson, Kristen
AU - Bar-Natan, Michal
AU - Pérez-Ladaga, Albert
AU - Zaneveld, Jacques
AU - Wang, Hui
AU - Caughey, Bennett
AU - Stojanov, Petar
AU - Getz, Gad
AU - Garcia-Manero, Guillermo
AU - Kantarjian, Hagop
AU - Chen, Rui
AU - Stone, Richard M.
AU - Neuberg, Donna
AU - Steensma, David P.
AU - Ebert, Benjamin L.
N1 - Publisher Copyright:
© 2014 by The American Society of Hematology.
PY - 2014/10/23
Y1 - 2014/10/23
N2 - Only a minority of myelodysplastic syndrome (MDS) patients respond to hypomethylating agents (HMAs), but strong predictors of response are unknown. We sequenced 40 recurrently mutated myeloid malignancy genes in tumor DNA from 213 MDS patients collected before treatment with azacitidine (AZA) or decitabine (DEC). Mutations were examined for association with response and overall survival. The overall response rate of 47% was not different between agents. Clonal TET2 mutations predicted response (odds ratio [OR] 1.99, P = .036) when subclones unlikely to be detected by Sanger sequencing (allele fraction <10%) were treated as wild-type (WT). Response rates were highest in the subset of TET2 mutant patients without clonal ASXL1 mutations (OR 3.65, P = .009). Mutations of TP53 (hazard ratio [HR] 2.01, P = .002) and PTPN11 (HR 3.26, P = .006) were associated with shorter overall survival but not drug response. Murine-competitive bone marrow transplantation followed by treatment with AZA demonstrated that Tet2-null cells have an engraftment advantage over Tet2-WT cells. AZA significantly decreased this advantage for Tet2-null cells (P = .002) but not Tet2-WT cells (P = .212). Overall, Tet2 loss appears to sensitize cells to treatment with AZA in vivo, and TET2 mutations can identify patients more likely to respond to HMAs.
AB - Only a minority of myelodysplastic syndrome (MDS) patients respond to hypomethylating agents (HMAs), but strong predictors of response are unknown. We sequenced 40 recurrently mutated myeloid malignancy genes in tumor DNA from 213 MDS patients collected before treatment with azacitidine (AZA) or decitabine (DEC). Mutations were examined for association with response and overall survival. The overall response rate of 47% was not different between agents. Clonal TET2 mutations predicted response (odds ratio [OR] 1.99, P = .036) when subclones unlikely to be detected by Sanger sequencing (allele fraction <10%) were treated as wild-type (WT). Response rates were highest in the subset of TET2 mutant patients without clonal ASXL1 mutations (OR 3.65, P = .009). Mutations of TP53 (hazard ratio [HR] 2.01, P = .002) and PTPN11 (HR 3.26, P = .006) were associated with shorter overall survival but not drug response. Murine-competitive bone marrow transplantation followed by treatment with AZA demonstrated that Tet2-null cells have an engraftment advantage over Tet2-WT cells. AZA significantly decreased this advantage for Tet2-null cells (P = .002) but not Tet2-WT cells (P = .212). Overall, Tet2 loss appears to sensitize cells to treatment with AZA in vivo, and TET2 mutations can identify patients more likely to respond to HMAs.
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U2 - 10.1182/blood-2014-06-582809
DO - 10.1182/blood-2014-06-582809
M3 - Article
C2 - 25224413
AN - SCOPUS:84908247072
SN - 0006-4971
VL - 124
SP - 2705
EP - 2712
JO - Blood
JF - Blood
IS - 17
ER -