RUNX1 Upregulation by Cytotoxic Drugs Promotes Apoptosis

TY - JOUR

T1 - RUNX1 Upregulation by Cytotoxic Drugs Promotes Apoptosis

AU - Speidel, Daniel

AU - Wellbrock, Jasmin

AU - Abas, Melissa

N1 - ©2017 American Association for Cancer Research.

PY - 2017/12/15

Y1 - 2017/12/15

N2 - Mutations in theRUNX1gene have been associated with chemotherapy resistance and poor prognosis in patients with acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia, and myelodysplastic syndromes. However, the underlying mechanisms connecting RUNX1 to the success of therapy remain elusive. Here we explore the hypothesis that RUNX1 is directly involved in the response of hematopoietic cells to cytotoxic agents. RUNX1 was upregulated posttranscriptionally by cytotoxic agents in C57BL/6 micein vivoand hematopoietic cell lines. Upregulation was also seen in primary human AML cells after treatment with cytarabinein vitroUpon overexpression, RUNX1 restricted proliferation, promoted apoptosis, and augmented the DNA damage response. This unknown activity of RUNX1 required an intact runt homology domain (RHD), a domain where most leukemia-associated point mutations cluster. Consistent with this, two RHD-defective RUNX1 proteins lacked any antiproliferative or apoptotic activity, and RHD-defective (K83N, N109D) mutant RUNX1 conferred resistance to ionizing radiation when overexpressed in Ba/F3 cells under certain conditions. Our experiments reveal a novel function of RUNX1 and offer an explanation for the link betweenRUNX1mutations and chemotherapy and radiation resistance. Moreover, these data suggest that pharmacologic modulation of RUNX1 might be an attractive new approach to treat hematologic malignancies.Cancer Res; 77(24); 6818-24. ©2017 AACR.

AB - Mutations in theRUNX1gene have been associated with chemotherapy resistance and poor prognosis in patients with acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia, and myelodysplastic syndromes. However, the underlying mechanisms connecting RUNX1 to the success of therapy remain elusive. Here we explore the hypothesis that RUNX1 is directly involved in the response of hematopoietic cells to cytotoxic agents. RUNX1 was upregulated posttranscriptionally by cytotoxic agents in C57BL/6 micein vivoand hematopoietic cell lines. Upregulation was also seen in primary human AML cells after treatment with cytarabinein vitroUpon overexpression, RUNX1 restricted proliferation, promoted apoptosis, and augmented the DNA damage response. This unknown activity of RUNX1 required an intact runt homology domain (RHD), a domain where most leukemia-associated point mutations cluster. Consistent with this, two RHD-defective RUNX1 proteins lacked any antiproliferative or apoptotic activity, and RHD-defective (K83N, N109D) mutant RUNX1 conferred resistance to ionizing radiation when overexpressed in Ba/F3 cells under certain conditions. Our experiments reveal a novel function of RUNX1 and offer an explanation for the link betweenRUNX1mutations and chemotherapy and radiation resistance. Moreover, these data suggest that pharmacologic modulation of RUNX1 might be an attractive new approach to treat hematologic malignancies.Cancer Res; 77(24); 6818-24. ©2017 AACR.

KW - Adult

KW - Animals

KW - Apoptosis

KW - Cells, Cultured

KW - Core Binding Factor Alpha 2 Subunit

KW - Cytotoxins

KW - Drug Resistance, Neoplasm

KW - Female

KW - Gene Expression Regulation

KW - Humans

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Point Mutation

KW - Up-Regulation

KW - Journal Article

U2 - 10.1158/0008-5472.CAN-17-0319

DO - 10.1158/0008-5472.CAN-17-0319

M3 - SCORING: Journal article

C2 - 29055018

VL - 77

SP - 6818

EP - 6824

JO - CANCER RES

JF - CANCER RES

SN - 0008-5472

IS - 24

ER -