Addiction of t(8;21) and inv(16) Acute Myeloid Leukemia to Native RUNX1
Menée sur des lignées cellulaires, cette étude met en évidence le rôle joué par la protéine RUNX1 dans le développement d'une leucémie myéloïde aiguë associée aux anomalies chromosomiques t(8:21) et inv(16)
The t(8;21) and inv(16) chromosomal aberrations generate the oncoproteins AML1-ETO (A-E) and CBF
β-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.
"The t(8;21) Kasumi-1 and inv(16) ME-1 cell lines are addicted to native RUNX1 "RUNX1 expression evades A-E- or C-S-mediated apoptosis of leukemic cell lines "RUNX1 regulates expression of mitotic checkpoint genes in Kasumi-1 AML cell line "Native RUNX1 facilitates leukemia development The t(8;21) and inv(16) chimeric oncogenes are major etiological drivers of human acute myeloid leukemia. However, the function of native RUNX1 in these leukemias has remained unknown. Groner and colleagues demonstrate that expression of wild-type RUNX1 is essential for t(8;21) and inv(16) leukemogenesis. Reducing RUNX1 activity destines the leukemic cells for apoptosis. Importantly, an active RUNX1 allele is usually preserved in t(8;21) or inv(16) patients, whereas, in other leukemias, it is frequently inactivated, underscoring the significance of this leukemic cell addiction to RUNX1.
http://linkinghub.elsevier.com/retrieve/pii/S2211124713004610