Senescence induction in human fibroblasts and hematopoietic progenitors by leukemogenic fusion proteins.
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.
Wajapeyee
Narendra
N
Howard Hughes Medical Institute and Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01606, USA.
Wang
Shu-Zong
SZ
Serra
Ryan W
RW
Solomon
Peter D
PD
Nagarajan
Arvindhan
A
Zhu
Xiaochun
X
Green
Michael R
MR
D017209:Apoptosis / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics*; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology* / Q000502:physiology; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D019337:Hematologic Neoplasms / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology; D006801:Humans; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D000075142:RUNX1 Translocation Partner 1 Protein; D012190:Retroviridae / Q000235:genetics; D014161:Transduction, Genetic
C107844:AML1-ETO fusion protein, human; C095514:CBFbeta-MYH11 fusion protein; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D016044:Fusion Proteins, bcr-abl