Biology subjects

Mizutani, S.

Publications and source records attributed to Mizutani, S..

2 recordsLinked to original sources

bioRxiv2022

Deletion of the transcriptional regulator TFAP4 accelerates c-MYC-driven lymphomagenesis

Many lymphoid malignancies arise from deregulated c-MYC expression in cooperation with additional genetic lesions. While many of these cooperative genetic lesions have been discovered, DNA sequence data suggest that many more do exist. However, their contributions to c-MYC driven lymphomagenesis have not yet been investigated. We identified TFAP4 as a potent suppressor of c-MYC driven lymphoma development in a previous genome-wide CRISPR knockout screen in primary cells in vivo (Mizutani et al, 2022). CRISPR deletion of TFAP4 in E-MYC transgenic hematopoietic stem and progenitor cells (HSPCs) significantly accelerated c-MYC-driven lymphoma development in mice. TFAP4 deficient E-MYC lymphomas all arose at the pre-B cell stage. Characterization of the transcriptional profile of pre-leukemic pre-B cells in E-MYC/Cas9/sgTFAP4 transplanted mice, revealed that TFAP4 deletion reduced expression of several master regulators of B cell differentiation, such as Spi1, SpiB and Pax5, which all have been shown to be bound by TFAP4. We therefore conclude that loss of TFAP4 leads to a block in differentiation during early B cell development, causing accelerated c-MYC-driven lymphoma development.

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↗