CRISPR Technique Shows New Protein Enzymatic Function in Acute Myeloid Leukemia


Investigators used a CRISPR technique to expose weaknesses in the acute myeloid leukemia enzyme that many drugs target.

In a paper published in Nature Chemical Biology, Harvard University assistant professor of Chemistry and Chemical Biology, Brian Liau, used a new gene-editing technique to expose more intimate details of why certain acute myeloid leukemia (AML) drugs sometimes fail in certain individuals and disproved previous assumptions regarding how they work.

Investigators focused on a specific sub-type of AML, which has mutated genes that cause a shift in a blood cell’s epigenetic state, leading to uncontrollable growth. According to the press release, new drugs target the enzymes that control the conversation between cells in order to ultimately reverse this malfunction. It has been determined that the enzyme target for AML is called lysine-specific histone demethylase 1 (LSD1), however, LSD1-targeting drugs rarely work, according to the study.

Investigators studied the “essential” portions of the enzyme in order to halt the protein, and therefore the disease, from uncontrollable growth. In order to do this, they used CRISPR-scanning, a gene-editing tool capable of making precise cuts in the genetic code (DNA).

The investigators used CRISPR to execute systematic but random slices in many AML-relevant genes at once. Afterwards, they were able to classify the weaknesses within the LSD1 so that the drugs can more easily target them.

In order to avoid strengthening the mutations, Lau and his colleagues examined how a drug interacts with each mutant, a technique called CRISPR-suppressor scanning. It is their belief that developers can use the information about the proliferation or suppression of malignant growth to subvert the protein’s new defenses.

Regarding the CRISPR-suppressor scanning, Lau said that tweaking the drug can create “bumps” or “holes” in the protein.

“If the bump-hole complement each other, we can tease this information apart with the methodology,” he said.

The study found that drugs targeting LSD1 shut down the protein's enzymatic function, but this function is not as critical to cancer growth as previously assumed. It also showed that the drugs can cut off communication between LSD1 and a transcription factor (GFI1B).

According to the press release, although the drugs worked because they disrupted both actions some of the time, Lau and his colleagues’ technique demonstrated that LSD1-GFI1B relationship is the most critical for AML survival. It could also explain why certain AML subtypes rely so heavily on LSD1.

The investigators hope that armed with this new information, drug developers can focus their work, hasten drug development, and produce a more targeted treatment, according to the release.

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