How Proteins in Acute Myeloid Leukemia Support Precision Medicine

September 14, 2021 - Sanford Burnham Prebys Medical Discovery Institute scientists discovered that the protein RNF5 plays an unusual role in acute myeloid leukemia (AML). By targeting the specific protein, researchers could advance AML treatment through precision medicine.

Going in a different direction than its expected role, RNF5 binds with a second protein called RBBP4 to control the expression of the genes impacted in AML.

“AML cells are highly dependent on the RNF5 protein,” director of the NCI-designated Cancer Center at Sanford Burnham Prebys and senior author of the paper, Ze’ev Ronai PhD, said in a press release.

“If we inhibit it, AML cells don’t survive. We can also use RNF5 levels to stratify patients for specific treatments. For example, if AML patients have low levels of RNF5 or RBBP4, they respond better to HDAC inhibitors, which are targeted treatments already used in the clinic.”

The lab has studied RNF5 for around ten years, primarily in breast and skin cancers. The research team then became interested in the protein’s role in AML when they observed that AML patients with high RNF5 levels often had poor outcomes.

In this study, the lab worked collaboratively with clinicians at Scripps MD Anderson in La Jolla, the Rambam Health Care Campus in Israel, and other leading scientists to generate the findings.

Normally, RNF5 helps mark other proteins for destruction. However, the researcher indicated that the RNF5 picks up a different skill when interacting with AML cells, partnering with the epigenetic regulator RBBP4. Instead of destroying it, RNF5 modifies RBBP4 to control the expression of genes associated with AML growth.

“It was quite surprising for us to find this ubiquitin ligase is actually regulating gene transcription in AML,” said Ali Khateb, PhD, postdoctoral researcher and first author on the paper.

“Ubiquitination improves recruitment of this epigenetic regulator to target genes. When you don’t have RNF5 in the cells, there is less recruitment of RBBP4 to the target genes, leading to their increased expression — and this inhibits AML growth.”

The researchers continued to collect evidence that RNF5 and RBBP4 work collaboratively to drive AML. By analyzing patient blood samples from the United States and Israel, the team confirmed that patients with high RNF5 levels have poor outcomes.

Additionally, they also showed that animals injected with cells that are inhibited for RNF5 had delayed leukemia development and longer survival rates. Continued work showed that inhibiting RBBP4 created the same results.

According to Khateb, these findings could have several therapeutic ramifications. By inhibiting RNF5, scientists could improve targeted therapies, advancing precision medicine.

“Patients with lower levels of either RNF5 or RBBP4 will probably respond better to HDAC inhibitors,” said Ronai. “We may be able to identify which AML patients will respond to these treatments based on their RNF5 or RBBP4 expression.”