Nature Sub-Journal: Gene editing technology can accurately replicate aggressive lymphoma

A powerful new genome editing technology that enables researchers to replicate human diseases with unprecedented accuracy promises to revolutionize the drug development process
for a range of cancers.

The technology, advanced by the WEHI team, could activate any gene — including those already silenced — to explore new drug targets and the causes
of resistance at an unparalleled level.

The researchers used this unique technique to replicate an aggressive lymphoma for the first time, and they used the technique to identify a gene responsible for triggering resistance to a new treatment for blood cancers currently in use in Australia
.

Study Summary:

• The researchers enhanced powerful genome editing techniques, created one of the most accurate double-strike lymphoma (DHL) models, and tested drugs against the disease with unprecedented success
  .

  
  

• The model reveals for the first time how a key protein triggers resistance to venetoclax
  .

  
  

• The new technology could be used to simulate a range of other human diseases that have never been replicated before, which could lead to the discovery of new drug targets for these diseases
  .

  
  

Lymphoma is the most common blood cancer in Australia, with around 6500 Australians diagnosed with lymphoma
each year.

For the first time, the team was able to enhance a genome editing technique called CRISPR activation to precisely simulate DHL
.

Professor Herold, who has established and leads one of Australia's most advanced CRISPR laboratories at WEHI, said: "Without the ability to model the disease, there is no opportunity to properly test which drug is effective
for this disease in the clinic.

"This technology is a game-changer for the scientific community and clinical staff, as it allows us to simulate diseases like DHL and properly test drug treatments
against them for the first time.

"This is important when you think that using this tool can better simulate too many human diseases
.

Engineering resistance

Venetoclax is the result of research by WEHI in collaboration with Roche, Genentech (a member of the Roche Group) and AbbVie, based on the Institute's groundbreaking scientific findings
over 30 years.

The anti-cancer drug is based on a discovery by WEHI in the late 1980s that a protein called BCL-2 can help cancer cells survive
indefinitely.

A1 is a survival-promoting protein
of the BCL-2 family.

While A1 has long been thought to play an important role in cancer development, PhD student and first author Yexuan Deng says this has not been proven
until now.

"Since DHL lymphoma in our model can be killed by venetoclax, we were able to use this to demonstrate for the first time that A1 is a major factor in drug resistance to this drug," Yexuan Deng said
.

While cancers are often caused by turning on genes, researchers can basically only turn them
off in previous disease models.

Project leader Associate Professor Gemma Kelly said the team was able to design drug resistance because their model could activate any gene — even those that had already been silenced
.

Associate Professor Kelly said: "We used the unprecedented ability of this model to initiate A1, which allowed us to confirm that this protein is a resistance driver
.
"

"Our study will allow more genes to be activated in other models to better understand cancer drivers and, more importantly, identify other causes
of drug resistance.
"

Co-first author Dr.
Sarah Diepstraten said the findings show that A1 is a promising drug target for DHL
.

Dr Dippstratten said: "This finding is because we were able to create a model for DHL that allows us to turn on any gene
.
"

"This demonstrates the unparalleled power
of our technology in simulating human disease and exploring why drug targets are effective or failing.
"

essay

Generate CRISPR activation mice, enabling invasive lymphoma modeling and inquiry of venetoclax resistance