Detection and targeting of splicing deregulation reveal a potential strategy for pAML therapy

Pediatric acute myeloid leukemia or pAML is a childhood blood cancer, one that has proved confounding to clinicians and researchers, with a high relapse rate and relatively few identified genetic mutations (compared to the adult version) that might explain its cause.

In a new study, published in the March 7, 2023 issue of Cell Reports, an international team led by scientists and physicians at University of California San Diego School of Medicine deployed an array of analytical and gene-splicing tools to parse more deeply the mysteries of mutation in pAML.

Compared to adult AML, pediatric AML is associated with relatively few known mutations, which likely stems from the fact that children have not yet been much exposed to environmental factors that damage DNA."

Catriona Jamieson, MD, PhD, senior study author, professor of medicine, director of the Sanford Stem Cell Institute and a hematologist specializing in blood disorders

"Our hypothesis was that the drivers were not genomic alterations, but rather occurred within transcriptomic and epitranscriptomic processes."

The transcriptome describes all of the RNA expressed by genes in an organism, such as a person. RNA is used to convey the genetic (DNA) information needed to make proteins and perform or regulate cellular functions. Transcriptomics is used to learn how genes are turned on and off in different cells and how that may be linked to certain diseases. The epitranscriptome refers to all of the modifications to RNA that occur within a cell.

In their study, Jamieson and colleagues at UC San Diego and in The Netherlands pinpointed a deregulation in splicing -; part of the process of decoding gene instructions into proteins -; that causes a therapeutic vulnerability to a small molecule splicing inhibitor called Rebecsinib.

In research published last month, Jamieson and colleagues reported that Rebecsinib, an experimental drug, reversed malignant hyper-editing by an inflammation-induced protein known as ADAR1 p150, which promotes immune silencing, metastasis and therapeutic resistance in 20 different cancer types, including leukemia.

"Our findings suggest a new approach to detecting and targeting therapy-resistant leukemia stem cells in pediatric AML and other cancer stem cells that become recalcitrant to treatment as a consequence of this splicing deregulation," Jamieson said.