Breaking New Ground With Blood Cancers Through the Lens of Splicing Factor Mutations

A decade ago, somatic mutations—those that occur after conception—in genes encoding RNA splicing factors were found to be key drivers of the development of myelodysplastic syndrome (MDS) in more than 50 percent of patients with the severe blood disorder. However, mouse models hold limitations in shedding light on the downstream disease drivers of blood cancers. So Eirini Papapetrou, MD, PhD, Professor of Oncological Sciences at the Icahn School of Medicine at Mount Sinai, came up with a new model that enables new findings.

Dr. Papapetrou and her lab have developed the first induced pluripotent stem cell (iPSC) models of MDS, as well as acute myeloid leukemia (AML). The models could highlight the complex mechanisms by which splicing factor mutations trigger oncogenesis and, just as importantly, how they could potentially be targeted by new or existing therapeutics.

“We’ve taken a multipronged approach by characterizing in great detail the splicing changes that mutations cause in cells, and by investigating how we could reverse or even cure the disease by targeting dysregulated genes or isoforms with inhibitors, degraders, or other therapies,” says Dr. Papapetrou, who originally trained as a hematologist.

Mount Sinai investigators, in collaboration with researchers at the University of California San Diego School of Medicine, focused on the SRSF2 and U2AF1 genes in a study. They generated models of the gene mutations using iPSCs, then turned these engineered cells into hematopoietic progenitor cells, which are the relevant cell type in blood cancers, in order to perform splicing and RNA binding analyses.

The study, reported in Cancer Discovery in March 2022, found—for the first time—that mutations in the two genes converge on a long isoform of the GNAS gene. The long isoform, in turn, appears to drive MDS by encoding a hyperactive long form of the stimulatory G protein alpha subunit, which activates extracellular signal-regulated kinase (ERK) and/or mitogen-activated protein kinase (MAPK) signaling. ERK and MAPK pathways are involved in hematopoiesis, or the formation of blood cellular components.

Researchers found that the alternative version of the protein created by the long GNAS isoform, with its activated ERK signaling, can be targeted by mitogen-activated protein kinase (MEK) inhibitors, a class of drugs that includes treatments already approved by the U.S. Food and Drug Administration.

Dr. Papapetrou’s team is trying to set up a clinical trial to determine if the MEK inhibitors will result in superior clinical outcomes for MDS patients with SRSF2 and U2AF1 mutations. “We also want to determine if mutant cells are sensitive to not just MEK inhibition, but to inhibition of the GNAS long isoform itself,” she says. “This could have significant therapeutic implications for MDS and other splicing factor mutant neoplasms.”

As part of its groundbreaking work with myeloid malignancies, the Papapetrou laboratory is also investigating, with the help of recent grants of $600,000 from the Edward P. Evans Foundation and $3.4 million from the National Cancer Institute, the role of mutations in epigenetic regulators in the pathogenesis of MDS. More specifically, the project is designed to study the cellular effects of the three most common clonal hematopoiesis mutations that impact genes regulating to the epigenome: DNMT3A, TET2, and ASXL1.

Over the long term, this work could lead to the identification of biomarkers to monitor patients with clonal hematopoiesis mutations and inform risk estimates of progression to myeloid malignancy and other morbidities.

“In the shorter term we are trying to understand how mutations in genes that regulate the epigenome drive the clonal expansion of these cells in a pre-leukemic state,” Dr. Papapetrou says. “Once we have that knowledge and can effectively target these mutations, the potential exists to prevent this cancer, which has a very poor prognosis, from ever occurring in patients.”