From fluffy, elusive protein to a possible target for a drug against an aggressive form of acute leukemia. The research group of Prof Ruud Delwel from Erasmus MC discovered a way to inhibit leukemia cells in a culture container and in laboratory animals with the help of artificial intelligence.
Bone marrow cells of mice with acute myeloid leukemia
The team found a possible brake for a specific form of acute myeloid leukemia, or AML. This is an aggressive form of AML in which the EVI1 gene is activated. About 3 to 4 percent of all AML patients have this untreatable subtype. EVI1 is a transcription factor: a protein that is located in the cell nucleus and activates other genes.
'Much is still unknown about the transcription factor EVI1, but our research shows that EVI1 needs a different protein to cause leukemia,' says Dorien Pastoors, PhD candidate in the group of Prof Ruud Delwel at the Hematology department of Erasmus MC. Pastoors and her colleagues, namely Eric Bindels and Marije Havermans, discovered that this other protein is CTBP.
The next step was to investigate how exactly EVI1 and CTBP fit together, like a key in a lock. This was not an easy task. 'Transcription factors are very fluid,' says Pastoors. 'They don't have much structure.' And to find an opportunity, you actually need structure. “You can imagine that your key will not work properly with a fluffy lock,” Pastoors explains.
Artificial intelligence
The researchers therefore used the AI model AlphaFold to predict the 3D structure of EVI1. 'AI models are much better at this than the models we used before. This really is a kind of landslide,' says Pastoors. 'We have found a part of EVI1 that is not sturdy in itself, but that is held by CTBP.' This part of EVI1 consists of the five amino acids called "PLDLS".
Using artificial intelligence, the researchers found the place where the proteins EVI1 (brown) and CTBP2 (blue) bind to each other. The binding site consists of the five amino acids called PLDLS.
Now that the team knew how EVI1 and CTBP bind, they could look for a way to break the connection. 'We have found an experimental key that can be used to break the bond. First in a breeding tank, but then also in laboratory animals,' says Pastoors. “Everyone always says that transcription factors are difficult to target, but we have now succeeded,” says Delwel.
The team developed a small piece of protein; a PLDLS inhibitor. This inhibitor binds to CTBP, preventing EVI1 from doing so. In mice, the PLDLS inhibitor was shown to stop the growth of AML cells. For the mouse tests, Pastoors worked with researchers from Amsterdam, London and Heidelberg.
Proof-of-concept
This research is a proof-of-concept study published in Science Advances. Delwel: 'This is the first time that a study has shown that an interaction between the transcription factor EVI1 and a cofactor can be broken. And that this helps against AML growth. But we are still a long way from finding a cure for EVI1-dependent AML. In this study, the mice received AML cells that already contained the inhibitor. To treat a patient, you must first get the inhibitor into the leukemia cell. “We are now working on that research,” says Pastoors. 'Together with researchers from Leiden, we are developing means that we can get into the cell.' How long does it take before this reaches the patient? “I don't dare to make any statements about that,” says Delwel.
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