Biology subjects

Turna, A.

Publications and source records attributed to Turna, A..

3 recordsLinked to original sources

bioRxiv2025

MYC-induced oncogenesis is dependent on acidic patches within its N-terminal intrinsically disordered domain.

MYC is one of the most enticing therapeutic targets for cancer but clinical-grade inhibitors are still lacking. By site-saturation mutagenesis screening, we identified several evolutionarily conserved acidic patches within the intrinsically-disordered MYC N-terminus that were confirmed to be functionally essential in different cell models and in vivo. Beyond modulating MYCs global transcriptional activity, these negatively charged patches regulate the interaction with chromatin-modifying complexes including those with histone acetyl-transferase activity. One of the key interactions is established with the co-factor TRRAP, a subunit shared between several Histone Acetyl-Transferase complexes. The protein-protein binding between MYC and TRRAP predominantly relies on two of the N-terminal negative clusters that are located outside MYC-Box-II (MBII) and drive oncogenesis. Our work identifies a new multivalent MYC subdomain that presents new therapeutic vulnerabilities providing invaluable insights for the development of new therapeutic approaches.

cancer biology↗

bioRxiv2024

Focal Deletions of a Promoter Tether Activate the IRX3 Oncogene in T Cell Acute Lymphoblastic Leukemia

Oncogenes can be activated in cis through multiple mechanisms including enhancer hijacking events and noncoding mutations that create enhancers or promoters de novo. These paradigms have helped parse somatic variation of noncoding cancer genomes, thereby providing a rationale to identify noncanonical mechanisms of gene activation. Here we describe a novel mechanism of oncogene activation whereby focal copy number loss of an intronic element within the FTO gene leads to aberrant expression of IRX3, an oncogene in T cell acute lymphoblastic leukemia (T-ALL). Loss of this CTCF bound element downstream to IRX3 (+224 kb) leads to enhancer hijack of an upstream developmentally active super-enhancer of the CRNDE long noncoding RNA (-644 kb). Unexpectedly, the CRNDE super-enhancer interacts with the IRX3 promoter with no transcriptional output until it is untethered from the FTO intronic site. We propose that promoter tethering of oncogenes to inert regions of the genome is a previously unappreciated biological mechanism preventing tumorigenesis.

cancer biology↗

bioRxiv2023

ILC2 cells promote lung cancer and accumulate in tumors concomitantly with immune-suppressive cells in humans and mice

It is now clear that group 2 innate lymphoid cells (ILC2) play crucial and sometimes opposing roles in the lung, such as restoring barrier function and integrity after viral infections or, on the contrary, exacerbating inflammation and tissue damage in allergic asthma. However, their role in lung cancer is still unclear. Here, we report that human non-small cell lung cancer patients bear increased frequencies of ILC2s in tumors, normal lung tissue and peripheral blood (PB) as compared to PB from healthy donors (HDs). Frequencies of Foxp3+ regulatory T cells were also increased in NSCLC patients, concomitantly with ILC2s. In mice bearing heterotopic lung cancer, adoptive transfer of ILC2s led to increased tumor growth and reduced survival. The frequencies of monocytic myeloid-derived suppressor cells (M-MDSCs) were found to be increased in the tumors of mice that received ILC2s as compared to controls. Overall, our results indicate that ILC2 cells play a pro-tumoral role in lung cancer potentially by recruiting immune-suppressive cells to the tumors.

immunology↗