Addiction of t(8;21) and inv(16) acute myeloid leukemia to native RUNX1.
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-1(RX1-KD)) attenuates the cell-cycle mitotic checkpoint, leading to apoptosis, whereas knockdown of A-E in Kasumi-1(RX1-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.
Department of Molecular Genetics, Weizmann Institute of Science, 76100 Rehovot, Israel.
Oren
O
Ben-Ami
Dan
D
Friedman
Dena
D
Leshkowitz
Dalia
D
Goldenberg
Kira
K
Orlovsky
Niv
N
Pencovich
Joseph
J
Lotem
Amos
A
Tanay
Yoram
Y
Groner
D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D007446:Chromosome Inversion; D002885:Chromosomes, Human, Pair 16; D002887:Chromosomes, Human, Pair 18; D002891:Chromosomes, Human, Pair 21; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D014162:Transfection; D014178:Translocation, Genetic
D050676:Core Binding Factor Alpha 2 Subunit