RUNX-mediated growth arrest and senescence are attenuated by diverse mechanisms in cells expressing RUNX1 fusion oncoproteins
| Autor: | Anderson, Gail, Mackay, Nancy, Gilroy, Kathryn, Hay, Jodie, Borland, Gillian, McDonald, Alma, Bell, Margaret, Hassanudin, Siti Ayuni, Cameron, Ewan, Neil, James C., Kilbey, Anna |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
senescence
Oncogene Proteins Fusion Articles Cell Cycle Checkpoints leukemogenesis DNA-Binding Proteins Gene Expression Regulation Neoplastic RUNX1‐ETO Mice RUNX1 Translocation Partner 1 Protein Cell Line Tumor Proto-Oncogene Proteins hemic and lymphatic diseases Core Binding Factor Alpha 2 Subunit embryonic structures Animals Humans TEL‐RUNX1 Cellular Senescence Research Article Transcription Factors |
| Zdroj: | Journal of Cellular Biochemistry |
| ISSN: | 0730-2312 |
| Popis: | RUNX gene over‐expression inhibits growth of primary cells but transforms cells with tumor suppressor defects, consistent with reported associations with tumor progression. In contrast, chromosomal translocations involving RUNX1 are detectable in utero, suggesting an initiating role in leukemias. How do cells expressing RUNX1 fusion oncoproteins evade RUNX‐mediated growth suppression? Previous studies showed that the TEL‐RUNX1 fusion from t(12;21) B‐ALLs is unable to induce senescence‐like growth arrest (SLGA) in primary fibroblasts while potent activity is displayed by the RUNX1‐ETO fusion found in t(8;21) AMLs. We now show that SLGA potential is suppressed in TEL‐RUNX1 but reactivated by deletion of the TEL HLH domain or mutation of a key residue (K99R). Attenuation of SLGA activity is also a feature of RUNX1‐ETO9a, a minor product of t(8;21) translocations with increased leukemogenicity. Finally, while RUNX1‐ETO induces SLGA it also drives a potent senescence‐associated secretory phenotype (SASP), and promotes the immortalization of rare cells that escape SLGA. Moreover, the RUNX1‐ETO SASP is not strictly linked to growth arrest as it is largely suppressed by RUNX1 and partially activated by RUNX1‐ETO9a. These findings underline the heterogeneous nature of premature senescence and the multiple mechanisms by which this failsafe process is subverted in cells expressing RUNX1 oncoproteins. |
| Databáze: | OpenAIRE |
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