Biology subjects

Healey, G.

Publications and source records attributed to Healey, G..

2 recordsLinked to original sources

bioRxiv2022

Combined absence of TRP53 target genes ZMAT3, PUMA and p21 cause a high incidence of cancer in mice

Transcriptional activation of target genes is essential for TP53-mediated tumour suppression, though the roles of many TP53-activated target genes in tumour suppression remains poorly understood. Knockdown of ZMAT3 in haematopoietic stem/progenitor cells by shRNA caused leukaemia only with the concomitant absence of the pro-apoptotic BCL-2 family member PUMA and the CDK inhibitor p21. We were interested to further investigate the role of ZMAT3 in tumour suppression beyond the haematopoietic system. Therefore, we generated Zmat3 knockout and compound gene knockout mice, lacking Zmat3 and p21, Zmat3 and Puma or all three genes. Puma-/-p21-/-Zmat3-/- triple knockout mice developed tumours at a significantly higher frequency compared to wild type, Puma-/-Zmat3-/- or p21-/- Zmat3-/-deficient mice. Interestingly, we observed that the triple and Puma-/-Zmat3-/- double deficient animals succumbed to lymphoma, while p21-/-Zmat3-/- animals developed mainly solid cancers. This analysis suggests that in addition to ZMAT3 loss, additional TRP53-regulated processes must be disabled simultaneously for TRP53-mediated tumour suppression to fail. Interestingly, our findings also reveal that the absence of different TRP53 regulated tumour suppressive processes changes the tumour spectrum, which suggests that different TRP53 tumour suppressive pathways are more critical in different tissues.

cancer biology↗

bioRxiv2022

Genome-wide in vivo CRISPR screens identify GATOR1 as a TP53 induced tumour suppressor

Identifying tumor suppressor genes is predicted to inform on the development of novel strategies for cancer therapy. To identify new lymphoma driving processes that cooperate with oncogenic MYC (which is abnormally highly expressed in [~]70% of human cancers) we have used a genome-wide CRISPR knockout screen in E{micro}-Myc;Cas9 transgenic hematopoietic stem and progenitor cells in vivo. We discovered that loss of any of the GATOR1 complex components - NPRL3, DEPDC5, NPRL2 - significantly accelerated c-MYC-driven lymphoma development in mice. Low expression of the GATOR1 complex genes correlated with poor survival outcomes for human patients with high MYC- expressing cancers. Murine lymphomas lacking GATOR1 were highly sensitive to mTOR inhibitors as a single agent therapy, both in vitro and in vivo. These findings identify inhibition of mTORC1 as a potent tumor suppressive mechanism in c-MYC-driven lymphomagenesis and suggest a new avenue for therapeutic intervention in GATOR1-deficient lymphomas through mTOR inhibition. Key PointsO_LIIn vivo CRISPR/Cas9 whole genome knockout screens identified the GATOR1 complex as a potent suppressor of c-MYC-driven lymphomagenesis. C_LIO_LIGATOR1 deficiency in MYC-driven lymphomas confers sensitivity to mTOR inhibition, suggesting a novel therapeutic approach. C_LI

cancer biology↗