Title

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

Student Author(s)

Ryan W. Serra

UMMS Affiliation

Graduate School of Biomedical Sciences, Cancer Biology Program; Program in Gene Function and Expression; Program in Molecular Medicine

Publication Date

2010-06-17

Document Type

Article

Disciplines

Cancer Biology | Life Sciences | Medicine and Health Sciences

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.

DOI of Published Version

10.1182/blood-2009-09-245928

Source

Blood. 2010 Jun 17;115(24):5057-60. Epub 2010 Apr 26.

Journal/Book/Conference Title

Blood

Related Resources

Link to article in PubMed

PubMed ID

20421454

Link to Full Text

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