Abstract
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.
Highlights
The phenomenon of oncogene-induced-senescence (OIS) was first described in primary murine fibroblasts expressing oncogenic Ras[1] and despite early scepticism was firmly established as a physiologically relevant failsafe mechanism that protects against cancer development.[2,3,4,5] More recently it has become clear that oncogene-induced senescence is just one facet of cellular senescence that may result from a variety of stimuli that include DNA damage, tumor suppressor activation and epigenetic perturbation
RUNX1 is one of the most frequently involved genes in human leukemia where it is subject to a range of chromosomal translocations, loss of function mutations and copy number gains, while all three murine Runx genes act as targets for transcriptional activation by insertional mutagenesis in lymphoma models, highlighting the dualistic potential of RUNX factors to act as oncogenes or tumor suppressors according to context.[16]
Our findings demonstrate multiple mechanisms by which transformed cells escape from RUNX growth suppression and provide a rationale for the contrasting secondary collaborating mutations required for TEL-RUNX1 and RUNX1-ETO associated leukemias
Summary
The phenomenon of oncogene-induced-senescence (OIS) was first described in primary murine fibroblasts expressing oncogenic Ras[1] and despite early scepticism was firmly established as a physiologically relevant failsafe mechanism that protects against cancer development.[2,3,4,5] More recently it has become clear that oncogene-induced senescence is just one facet of cellular senescence that may result from a variety of stimuli that include DNA damage, tumor suppressor activation and epigenetic perturbation. RUNX1 is one of the most frequently involved genes in human leukemia where it is subject to a range of chromosomal translocations, loss of function mutations and copy number gains, while all three murine Runx genes act as targets for transcriptional activation by insertional mutagenesis in lymphoma models, highlighting the dualistic potential of RUNX factors to act as oncogenes or tumor suppressors according to context.[16] The archetypal chromosomal fusions involving RUNX1 are the t(8;21) translocation which results in C-terminal truncation of RUNX1 and fusion to ETO in acute myeloid leukemia and the t(12;21) translocation which fuses an almost complete RUNX1 isoform at its N-terminus to a truncated TEL/ETV6 moiety in childhood B-ALL.[17] These translocations appear as early events in leukemogenesis that often arise in utero, as indicated by their detection in neonatal blood spots.[18,19] Latency periods to detectable disease can be protracted, supporting the existence of long lived or stable parental clones requiring collaborating secondary mutations for leukemic progression.[18,20] Further evidence that RUNX1 is not a typical tumor suppressor is provided by the observations that leukemia cells require normal RUNX1 expressed from the unaffected allele for viability,[21] while progressing t(12;21) leukemias show sustained high level expression of RUNX1 and frequent copy number gains of chromosome 21.22,23. Our findings demonstrate multiple mechanisms by which transformed cells escape from RUNX growth suppression and provide a rationale for the contrasting secondary collaborating mutations required for TEL-RUNX1 and RUNX1-ETO associated leukemias
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