TY - JOUR
T1 - Addiction of t(8;21) and inv(16) Acute Myeloid Leukemia to Native RUNX1
AU - Ben-Ami, Oren
AU - Friedman, Dan
AU - Leshkowitz, Dena
AU - Goldenberg, Dalia
AU - Orlovsky, Kira
AU - Pencovich, Niv
AU - Lotem, Joseph
AU - Tanay, Amos
AU - Groner, Yoram
N1 - Funding Information:
We thank Dr. Daniela Amann-Zalcennstein and Dr. Shirely Horn-Saban for help with Illumina sequencing and gene expression data acquisition, Dr. Ziv Porat for ImageStream analysis, and Dr. Ditsa Levanon for helpful comments throughout this work. We thank Dr. Takashi Egawa for providing the anti-AP4 Ab, Prof. Alon Chen for the lentivirus vector, and Profs. Moshe Oren, Atan Gross, Eli Arama, Yaqub Hanna, Orly Reiner, Tsvee Lapidot, and Sigal Tavor for helpful suggestions and stimulating discussions. This study was supported by grants from the Israel Science Foundation and the European Research Council. A.T. is an incumbent of the Rich family WIS CDC.
PY - 2013/9/26
Y1 - 2013/9/26
N2 - The t(8;21) and inv(16) chromosomal aberrations generate the oncoproteins AML1-ETO (A-E) and CBFβ-SMMHC (C-S). The role of these oncoproteins in acute myeloid leukemia (AML) etiology has been well studied. Conversely, the function of native RUNX1 in promoting A-E- and C-S-mediated leukemias has remained elusive. We show that wild-type RUNX1 is required for the survival of t(8;21)-Kasumi-1 and inv(16)-ME-1 leukemic cells. RUNX1 knockdown in Kasumi-1 cells (Kasumi-1RX1-KD) attenuates the cell-cycle mitotic checkpoint, leading to apoptosis, whereas knockdown of A-E in Kasumi-1RX1-KD rescues these cells. Mechanistically, a delicate RUNX1/A-E balance involving competition for common genomic sites that regulate RUNX1/A-E targets sustains the malignant cell phenotype. The broad medical significance of this leukemic cell addiction to native RUNX1 is underscored by clinical data showing that an active RUNX1 allele is usually preserved in both t(8;21) or inv(16) AML patients, whereas RUNX1 is frequently inactivated in other forms of leukemia. Thus, RUNX1 and its mitotic control targets are potential candidates for new therapeutic approaches
AB - The t(8;21) and inv(16) chromosomal aberrations generate the oncoproteins AML1-ETO (A-E) and CBFβ-SMMHC (C-S). The role of these oncoproteins in acute myeloid leukemia (AML) etiology has been well studied. Conversely, the function of native RUNX1 in promoting A-E- and C-S-mediated leukemias has remained elusive. We show that wild-type RUNX1 is required for the survival of t(8;21)-Kasumi-1 and inv(16)-ME-1 leukemic cells. RUNX1 knockdown in Kasumi-1 cells (Kasumi-1RX1-KD) attenuates the cell-cycle mitotic checkpoint, leading to apoptosis, whereas knockdown of A-E in Kasumi-1RX1-KD rescues these cells. Mechanistically, a delicate RUNX1/A-E balance involving competition for common genomic sites that regulate RUNX1/A-E targets sustains the malignant cell phenotype. The broad medical significance of this leukemic cell addiction to native RUNX1 is underscored by clinical data showing that an active RUNX1 allele is usually preserved in both t(8;21) or inv(16) AML patients, whereas RUNX1 is frequently inactivated in other forms of leukemia. Thus, RUNX1 and its mitotic control targets are potential candidates for new therapeutic approaches
UR - http://www.scopus.com/inward/record.url?scp=84884583958&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2013.08.020
DO - 10.1016/j.celrep.2013.08.020
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C2 - 24055056
AN - SCOPUS:84884583958
SN - 2211-1247
VL - 4
SP - 1131
EP - 1143
JO - Cell Reports
JF - Cell Reports
IS - 6
ER -
