Interview with Dr. Neil from the University of Glasgow

Oncotarget published " Addiction to Runx1 is partially attenuated by loss of p53 in the E μ-Myc lymphoma model " which reported that the Runx genes function as dominant oncogenes that collaborate potently with Myc or loss of p53 to induce lymphoma when overexpressed.

Here they examined the requirement for basal Runx1 activity for tumor maintenance in the E μ-Myc model of Burkitt 's lymphoma .

While normal Runx1fl/fl lymphoid cells permit mono-allelic deletion, primary E μ-Myc lymphomas showed selection for retention of both alleles and attempts to enforce deletion in vivo led to compensatory expansion of p53null blasts retaining Runx1. Surprisingly, Runx1 could be excised completely from established E μ-Myc lymphoma cell lines in vitro without obvious effects on cell phenotype.

Transcriptome analysis of Runx1-deleted cells revealed a gene signature associated with lymphoid proliferation, survival and differentiation, and included strong de-repression of recombination-activating genes, an observation that was mirrored in a panel of human acute leukemias where RUNX1 and RAG1,2 mRNA expression were negatively correlated.

Notably, despite their continued growth and tumorigenic potential, Runx1null lymphoma cells displayed impaired proliferation and markedly increased sensitivity to DNA damage and dexamethasone-induced apoptosis, the Oncotarget study concludes that validating Runx1 function as a potential therapeutic target in Myc-driven lymphomas regardless of their p53 status.

The Oncotarget study concludes that validating Runx1 function as a potential therapeutic target in Myc-driven lymphomas regardless of their p53 status

Dr. James C. Neil and Dr. Ewan Cameron both from The University of Glasgow said, "Runx1 encodes a transcription factor that plays a vital role in development of the haematopoietic system. "

Evidence that simple over-expression of any of the Runx gene family members can drive oncogenesis emerged first from mouse models, where it was shown that all three genes can act as targets for murine leukemia virus insertional mutagenesis and transcriptional activation in lymphoma.

Common targets in the E μ-Myc lymphoma model include Runx1 and Runx3, while all three members of the Runx family were identified as activation targets in CD2-MYC T-cell lymphomas.

In contrast to this catalogue of evidence of dominant oncogenic activity in lymphomagenesis, Runx1 deficient cells in chimeric mice develop T-cell lymphomas after treatment with ENU, suggesting that loss of Runx1 activity can also predispose to lymphoid malignancy.

RUNX1 is among the most over-expressed genes in childhood ALL and is highly amplified in a poor prognostic B-ALL subgroup while presumptive loss-of-function RUNX1 mutations have been observed in a small proportion of T-ALLs where network analysis further implicated RUNX1 as a candidate tumor suppressor.

These findings shed light on the paradoxical observation that Runx1 deficiency can also predispose to lymphoma but more importantly validate Runx1 function as a therapeutic target in p53 wild-type or mutant lymphomas.

The Neil/Cameron Research Team concluded in their Oncotarget Priority Research Paper that the finding that basal Runx1 activity is critical for Myc-driven lymphoma maintenance in vivo and that dependence is only partially attenuated in established cell lines lacking p53 is encouraging for ongoing efforts to target the Runx genes and their downstream effectors in cancer therapy.

Moreover, the increased sensitivity of Runx1-deleted cells to components of standard chemotherapeutic regimens in current use for lymphoma therapy suggests that these may be combined with Runx inhibition for greater efficacy.

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DOI - https://doi.org/10.18632/oncotarget.8554

Full text - https://www.oncotarget.com/article/8554/text/

Correspondence to - James C. Neil - [email protected] and Ewan Cameron - [email protected]

Keywords - Runx1, lymphoma, myc, oncogene addiction