A druggable target for AML: cell-surface RNA-binding proteins

In 2021, analysis led by Ryan Flynn, MD, PhD, and his mentor, Nobel laureate Carolyn Bertozzi, PhD, opened a brand new chapter in biology, characterizing a new kind of player on the cell surface: glycoRNAs. Extending this discovery recently in Cell, Flynn and colleagues confirmed that glycoRNAs kind extremely organized clusters with RNA-binding proteins on the cell floor. These clusters seem to manage communication between cells and their setting.

Now, reporting in Nature Biotechnology, Flynn’s workforce within the Stem Cell Program at Boston Kids’s Hospital and Dana-Farber/Boston Children’s Cancer and Blood Disorders Center reveal a primary software of this newfound biology: preventing most cancers.

With collaborators on the Cambridge (UK) Stem Cell Institute, led by Konstantinos Tzelepis, PhD, and Maria Eleftheriou, PhD, they present that one RNA-binding protein on the cell floor — NPM1 — could possibly be a potent, selective goal for treating acute myeloid leukemia (AML), in addition to stable tumors.

Concentrating on the NPM1 protein

AML, a quickly progressive blood most cancers, has been tough to focus on therapeutically as a result of a lot of its driving pathways are additionally important for non-cancerous cells, together with blood stem cells. “The illness could also be insensitive to current medicine, or sufferers could also be too frail to get classical therapeutics, as a result of the toxicity is simply too excessive,” says Flynn.

He and his colleagues zeroed in on NPM1 as a result of mutations within the NPM1 gene have been strongly implicated in grownup AML — driving about 60 p.c of instances not attributed to chromosomal abnormalities. Whereas NPM1 is often discovered contained in the cell, Flynn, Tzelepis, and colleagues confirmed that in malignant AML cells, it’s offered on the floor.

“The quantity of cell-surface NPM1 was greater than ten instances increased on leukemic cells as in comparison with wholesome cells,” says Flynn. “It was very strongly expressed on cells from almost each affected person we checked out. There was greater than a 100-fold distinction between cancerous and wholesome blood stem cells; regular blood stem cells have virtually no NPM1 on their floor.”

As a result of it’s a floor marker, NPM1 is well detectable with easy strategies, and will present a approach to monitor sufferers. However the true fantastic thing about NPM1 being on the cell floor is that it may be readily focused with broadly used brokers, resembling antibodies.

Utilizing a monoclonal antibody concentrating on NPM1, the researchers noticed strong anti-tumor exercise in a number of in vivo fashions of AML, whereas noncancerous blood cells and stem cells had been spared. In 4 separate mouse fashions of leukemia, the antibodies neutralized AML and extended survival with no obvious toxicity.

Most excitingly, the antibodies successfully focused leukemic stem cells in bone marrow samples and mouse fashions. “That is essential, as a result of a handful of leukemia stem cells can regenerate the most cancers even when it seems to be eradicated,” says Flynn.

What about different cancers?

The potential advantages of concentrating on NPM1 may lengthen to different cancers. The workforce examined 47 human and mouse stable tumor fashions and located that the majority had cell-surface NPM1 to various levels. Experiments in mice instructed that monoclonal antibodies concentrating on cell-surface NPM1 is perhaps efficient towards sure stable tumors, together with prostate and colorectal most cancers.

“Discovering cell-surface targets which are particular to malignancies however spared on wholesome tissue has been a protracted sought-after objective for immuno-oncology,” says Benson George, MD, PhD, within the Flynn Lab, who was co-first creator on the brand new paper with Eleftheriou. “Many cancers lack recognized molecular handles that may safely be leveraged to sign the immune system to assault. An awesome instance of that is colorectal most cancers, which is rising in incidence.”

In future work, the workforce plans to research why cells are bringing NPM1 to the floor, and to discover whether or not clusters of glycoRNA and RNA-binding proteins include different targetable molecules related to most cancers.

“We hypothesize that bringing NPM1 to the cell floor is in some way helpful for the tumor,” Flynn says. “That is actually a brand new class of tumor antigens.”

Boston Kids’s Hospital has filed patent purposes to guard this invention within the U.S. and international jurisdictions. Contact TIDO@childrens.harvard.edu for additional data.

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