First Author | Dong Y | Year | 2019 |
Journal | Leukemia | Volume | 33 |
Issue | 11 | Pages | 2585-2598 |
PubMed ID | 30967619 | Mgi Jnum | J:282083 |
Mgi Id | MGI:6370084 | Doi | 10.1038/s41375-019-0456-2 |
Citation | Dong Y, et al. (2019) SETD2 mutations confer chemoresistance in acute myeloid leukemia partly through altered cell cycle checkpoints. Leukemia 33(11):2585-2598 |
abstractText | SETD2, an epigenetic tumor suppressor, is frequently mutated in MLL-rearranged (MLLr) leukemia and relapsed acute leukemia (AL). To clarify the impact of SETD2 mutations on chemotherapy sensitivity in MLLr leukemia, two loss-of-function (LOF) Setd2-mutant alleles (Setd2(F2478L/WT) or Setd2(Ex6-KO/WT)) were generated and introduced, respectively, to the Mll-Af9 knock-in leukemia mouse model. Both alleles cooperated with Mll-Af9 to accelerate leukemia development that resulted in resistance to standard Cytarabine-based chemotherapy. Mechanistically, Setd2-mutant leukemic cells showed downregulated signaling related to cell cycle progression, S, and G2/M checkpoint regulation. Thus, after Cytarabine treatment, Setd2-mutant leukemic cells exit from the S phase and progress to the G2/M phase. Importantly, S and G2/M cell cycle checkpoint inhibition could resensitize the Mll-Af9/Setd2 double-mutant cells to standard chemotherapy by causing DNA replication collapse, mitotic catastrophe, and increased cell death. These findings demonstrate that LOF SETD2 mutations confer chemoresistance on AL to DNA-damaging treatment by S and G2/M checkpoint defects. The combination of S and G2/M checkpoint inhibition with chemotherapy can be explored as a promising therapeutic strategy by exploiting their unique vulnerability and resensitizing chemoresistant AL with SETD2 or SETD2-like epigenetic mutations. |