Senescence induction in human fibroblasts and hematopoietic progenitors by leukemogenic fusion proteins

Howard Hughes Medical Institute and Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01606, USA.
Blood (Impact Factor: 10.45). 06/2010; 115(24):5057-60. DOI: 10.1182/blood-2009-09-245928
Source: PubMed

ABSTRACT Hematologic malignancies are typically associated with leukemogenic fusion proteins, which are required to maintain the oncogenic state. Previous studies have shown that certain oncogenes that promote solid tumors, such as RAS and BRAF, can induce senescence in primary cells, which is thought to provide a barrier to tumorigenesis. In these cases, the activated oncogene elicits a DNA damage response (DDR), which is essential for the senescence program. Here we show that 3 leukemogenic fusion proteins, BCR-ABL, CBFB-MYH11, and RUNX1-ETO, can induce senescence in primary fibroblasts and hematopoietic progenitors. Unexpectedly, we find that senescence induction by BCR-ABL and CBFB-MYH11 occurs through a DDR-independent pathway, whereas RUNX1-ETO induces senescence in a DDR-dependent manner. All 3 fusion proteins activate the p38 MAPK pathway, which is required for senescence induction. Our results reveal diverse pathways for oncogene-induced senescence and further suggest that leukemias harbor genetic or epigenetic alterations that inactivate senescence induction genes.

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Available from: Narendra Wajapeyee, Aug 27, 2015
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    • "Although the activation of DDR by oncogene-induced hyper-replication has been shown by some groups as the key mediator of oncogene-induced senescence,31,32 other reports underline the independency of DDR in terms of senescence induction by some leukemogenic fusion proteins, such as BCR-ABL and CBFB-MYH11.33 Here, p38 kinase pathway followed by p16 induction plays a crucial role in the commitment to senescence. "
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