Genome-Wide Screening Approach Uncovers Genetic Brakes on Blood Cancer Growth

Australian researchers have used an innovative genome-wide screening approach to identify genes, and their encoded proteins, that play critical roles in the prevention of lymphoma development, revealing new potential treatment targets for these blood cancers. 

The study, published in Nature Communications today, has identified a group of proteins known as the GATOR1 complex as essential tumor suppressors. 

The GATOR1 complex normally functions as a 'brake' on cellular growth by regulating pathways that control cell growth and metabolism. When GATOR1 components are lost or defective, this protective mechanism fails, allowing cells to grow uncontrollably. 

The research is a collaboration between the Olivia Newton-John Cancer Research Institute (ONJCRI), WEHI, and the Peter MacCallum Cancer Centre. 

The team utilized sophisticated pre-clinical models of aggressive lymphoma to systematically test the function of all known genes in this complex. Their comprehensive screening approach revealed that when any of the GATOR1 genes are lacking, lymphoma development is dramatically accelerated, identifying the GATOR1 complex as a crucial suppressor of blood cancer development. 

Co-lead author Dr Margaret Potts said: "The best thing about performing a well-designed CRISPR screen is that you will always find something. 

"Our unbiased screening approach looked at all genes, rather than just a subset of them. By not limiting our investigation to known pathways, we found expected as well as unexpected tumor suppressor genes and pathways, such as GATOR1." 

Strikingly, existing drugs that target the same cellular pathways that GATOR1 typically controls were highly effective at slowing the growth of lymphomas in GATOR1-deficient pre-clinical models. 

These drugs have previously had limited success in cancer treatment, and this may be because researchers have not been able to identify which patients would respond well to these therapeutics. 

"Our paper begins the exploration into this precision medicine opportunity," shared Dr Potts. 

Prof Marco Herold, CEO of ONJCRI, Head of the La Trobe School of Cancer Medicine and senior author of the Nature Communications paper, said: 

"Our pre-clinical lymphoma model is driven by high levels of the oncogene MYC, an abnormality that can be found in ~70% of all human cancers. When GATOR1 is lacking, it removes a critical brake that normally slows MYC-driven malignancy. 

This exciting discovery provides a new insight into the development and sustained expansion of cancer, which we hope will underpin the development of more effective, targeted treatments for cancer." 

According to the Global Cancer Observatory, there were over 630,000 new cases of lymphoma worldwide in 2022, highlighting the urgent need for better understanding of the molecular mechanisms that drive this disease.

The research was led by Dr Margaret Potts, Dr Shinsuke Mizutani, and Dr Yexuan Deng, under the supervision of Prof Marco Herold, Prof Andreas Strasser (WEHI), and A/Prof Kristin Brown (Peter Mac).