Do RAB Proteins Play a Role in Development of Acute Myeloid Leukemia?

The findings:

Researchers from Children’s Hospital of Philadelphia found that the protein RAB27B is a safe and promising target for CBL or NRAS mutant malignancies, which are frequently identified in myeloid disorders, including acute myeloid leukemia (AML) and chronic myelomonocytic leukemia.

Why it matters:

Mutations in the RAS proteins are an important driver of myeloid disorders linked to NRAS gene mutations. RAS proteins control signaling pathways that contribute to cell growth via palmitoylation, a process in which fatty acids attach to protein residues called cysteines. This process allows the RAS proteins to be trafficked across cell membranes. The study findings show that the protein RAB27B controls NRAS palmitoylation and trafficking, highlighting future therapeutic strategies for RAS-driven cancers.

The RAB27B gene is linked to poor prognosis in AML and in several solid tumors. The new findings suggest that the gene plays a role in whether AML is sensitive to MEK inhibitors, which target the RAS/MEK/ERK signaling pathway. Several MEK inhibitors are already approved by the U.S. Food and Drug Association to treat several solid tumors and are under investigation for hematologic malignancies.

Who conducted the study:

Wei Tong, PhD, investigator in the Division of Hematology at CHOP, and professor of Pediatrics at the University of Pennsylvania Perelman School of Medicine, is the study’s senior author.

How they did it:

The researchers used quantitative mass spectrometry to conduct a proteomic study of leukemia cell lines. Proteomic studies are used to evaluate protein attributes and their cellular activities. They then worked with animal models to validate the findings. The researchers found that the RAB27B gene is upregulated in myeloid malignancies with CBL or JAK2 mutations, which further enhances the NRAS activity. When this gene is depleted in AML cell lines, oncogenic NRAS signaling is disrupted, prohibiting leukemia growth.

Quick thoughts:

“RAS mutations are among the most prevalent in human cancers, yet RAS proteins are notorious for their druggability,” Dr. Tong said. “This study revealed a novel mechanism of RAS regulation, which may open up new targets and vulnerabilities to drug RAS pathways in leukemia or cancer.”

What’s next:

Dr. Tong's work presents a link between RAB proteins and fundamental aspects of RAS signaling, implicating RAB27B as a target for future therapeutic strategies for RAS-driven cancers. Future investigations are warranted to discover specific inhibitors against RAB27B for the treatment of myeloid malignancies.

Where the study was published:

The study appeared in The Journal of Clinical Investigation.