TY - JOUR
T1 - TET2 and DNMT3A mutations exert divergent effects on DNA repair and sensitivity of leukemia cells to PARP inhibitors
AU - Maifrede, Silvia
AU - Le, Bac Viet
AU - Nieborowska-Skorska, Margaret
AU - Golovine, Konstantin
AU - Sullivan-Reed, Katherine
AU - Dunuwille, Wangisa M.B.
AU - Nacson, Joseph
AU - Hulse, Michael
AU - Keith, Kelsey
AU - Madzo, Jozef
AU - Caruso, Lisa Beatrice
AU - Gazze, Zachary
AU - Lian, Zhaorui
AU - Padella, Antonella
AU - Chitrala, Kumaraswamy N.
AU - Bartholdy, Boris A.
AU - Matlawska-Wasowska, Ksenia
AU - Marcantonio, Daniela Di
AU - Simonetti, Giorgia
AU - Greiner, Georg
AU - Sykes, Stephen M.
AU - Valent, Peter
AU - Paietta, Elisabeth M.
AU - Tallman, Martin S.
AU - Fernandez, Hugo F.
AU - Litzow, Mark R.
AU - Minden, Mark D.
AU - Huang, Jian
AU - Martinelli, Giovanni
AU - Vassiliou, George S.
AU - Tempera, Italo
AU - Piwocka, Katarzyna
AU - Johnson, Neil
AU - Challen, Grant A.
AU - Skorski, Tomasz
N1 - Publisher Copyright:
© 2021 American Association for Cancer Research
PY - 2021/10/1
Y1 - 2021/10/1
N2 - Somatic variants in TET2 and DNMT3A are founding mutations in hematological malignancies that affect the epigenetic regulation of DNA methylation. Mutations in both genes often co-occur with activating mutations in genes encoding oncogenic tyrosine kinases such as FLT3ITD, BCR-ABL1, JAK2V617F, and MPLW515L, or with mutations affecting related signaling pathways such as NRASG12D and CALRdel52. Here, we show that TET2 and DNMT3A mutations exert divergent roles in regulating DNA repair activities in leukemia cells expressing these oncogenes. Malignant TET2-deficient cells displayed downregulation of BRCA1 and LIG4, resulting in reduced activity of BRCA1/2-mediated homologous recombination (HR) and DNA-PK–mediated non-homologous end-joining (D-NHEJ), respectively. TET2-deficient cells relied on PARP1-mediated alternative NHEJ (Alt-NHEJ) for protection from the toxic effects of spontaneous and drug-induced DNA double-strand breaks. Conversely, DNMT3A-deficient cells favored HR/D-NHEJ owing to downregulation of PARP1 and reduction of Alt-NHEJ. Consequently, malignant TET2-deficient cells were sensitive to PARP inhibitor (PARPi) treatment in vitro and in vivo, whereas DNMT3Adeficient cells were resistant. Disruption of TET2 dioxygenase activity or TET2—Wilms’ tumor 1 (WT1)–binding ability was responsible for DNA repair defects and sensitivity to PARPi associated with TET2 deficiency. Moreover, mutation or deletion of WT1 mimicked the effect of TET2 mutation on DSB repair activity and sensitivity to PARPi. Collectively, these findings reveal that TET2 and WT1 mutations may serve as biomarkers of synthetic lethality triggered by PARPi, which should be explored therapeutically.
AB - Somatic variants in TET2 and DNMT3A are founding mutations in hematological malignancies that affect the epigenetic regulation of DNA methylation. Mutations in both genes often co-occur with activating mutations in genes encoding oncogenic tyrosine kinases such as FLT3ITD, BCR-ABL1, JAK2V617F, and MPLW515L, or with mutations affecting related signaling pathways such as NRASG12D and CALRdel52. Here, we show that TET2 and DNMT3A mutations exert divergent roles in regulating DNA repair activities in leukemia cells expressing these oncogenes. Malignant TET2-deficient cells displayed downregulation of BRCA1 and LIG4, resulting in reduced activity of BRCA1/2-mediated homologous recombination (HR) and DNA-PK–mediated non-homologous end-joining (D-NHEJ), respectively. TET2-deficient cells relied on PARP1-mediated alternative NHEJ (Alt-NHEJ) for protection from the toxic effects of spontaneous and drug-induced DNA double-strand breaks. Conversely, DNMT3A-deficient cells favored HR/D-NHEJ owing to downregulation of PARP1 and reduction of Alt-NHEJ. Consequently, malignant TET2-deficient cells were sensitive to PARP inhibitor (PARPi) treatment in vitro and in vivo, whereas DNMT3Adeficient cells were resistant. Disruption of TET2 dioxygenase activity or TET2—Wilms’ tumor 1 (WT1)–binding ability was responsible for DNA repair defects and sensitivity to PARPi associated with TET2 deficiency. Moreover, mutation or deletion of WT1 mimicked the effect of TET2 mutation on DSB repair activity and sensitivity to PARPi. Collectively, these findings reveal that TET2 and WT1 mutations may serve as biomarkers of synthetic lethality triggered by PARPi, which should be explored therapeutically.
UR - http://www.scopus.com/inward/record.url?scp=85116975591&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-20-3761
DO - 10.1158/0008-5472.CAN-20-3761
M3 - Article
C2 - 34215619
AN - SCOPUS:85116975591
SN - 0008-5472
VL - 81
SP - 5089
EP - 5101
JO - Cancer research
JF - Cancer research
IS - 19
ER -