New Yale study shows potential target for treating blood cancers
Researchers in the Halene lab at the School of Medicine have discovered a new pathogenic mechanism in hematological malignancies that could open doors in treatment.
Jessai Flores, Staff Illustrator
Researchers in the Halene lab at the Yale Cancer Center have published a new study that unveils the potential mechanism behind the progression of certain types of blood cancers.
The study focused on two out of three main types of hematological malignancies, or cancers of the blood: leukemia and myeloma. Giulia Biancon, postdoctoral associate in the Halene Lab, was the lead author of the study along with senior authors Toma Tebaldi, past adjunct assistant professor at the School of Medicine, and Stephanie Halene, chief of hematology at the Yale Cancer Center and professor of hematology.
“[The study involved] the development and application of a multi-omics approach that allows the investigation of aberrant RNA mechanisms at different levels,” Biancon wrote to the News. “This approach allowed us to observe the involvement of stress granule components and increased stress granule formation in U2AF1-mutant MDS/AML.”
This multi-omics approach allowed the researchers to view the effects of the genes of interest on different levels including the genome, proteome and transcriptome.
In the human body, myeloid cells are a subgroup of leukocytes, or white blood cells, that include cells such as granulocytes, monocytes, macrophages and dendritic cells. They circulate through the blood and lymphatic system and are rapidly recruited to sites of tissue damage and infection. Myelodysplastic syndromes, or MDS, are a group of disorders caused by poorly formed or dysfunctional blood cells and result from defective bone marrow, which is responsible for the formation of blood cells.
Acute myeloid leukemia, or AML, is a cancer of the blood and bone marrow where there is an excess of immature white blood cells. It is the most common type of acute leukemia in adults and progresses rapidly, with myeloid cells interfering with the production of normal white blood cells, red blood cells and platelets.
When researching the development of MDS and AML, the researchers investigated mutations in the splicing factor U2AF1, a protein which edits mRNA transcripts, which are found in 50 percent of patients with MDS and 10 percent of patients with AML. This provides a mechanism for the progression of blood cancers as mutations in this gene aid cancer cells in surviving extracellular and intracellular stresses.
“Ultimately, this reprogramming of splicing factor-RNA interactions modifies the composition and aggregation of the RNAs in the cell and facilitates the formation of stress granules, aggregations of RNAs and proteins that form when cells are ‘stressed’,” Tebaldi wrote to the News. “Therefore cells with these mutations may have a competitive advantage over ‘normal’ cells in stressful situations, such as tumors and the pharmacological treatments used to treat them.”
Splicing factors are cellular molecules necessary for the editing of mRNA transcripts, which are responsible for translating the proteins of the cell. When this processing and editing of mRNA is incomplete or erroneous, mistakes in the transcript remain and are translated into the proteins that are produced for all cell functions.
In the study, the researchers provided evidence for U2AF1 mutations’ role in altered mRNA binding and splicing and the production of stress granules. Stress granules are dense aggregations in the cell composed of proteins and RNAs that appear when the cell is under stress. Since mutations in the splicing factor lead to increased production of stress granules, mutated malignant cells have a better advantage of surviving and leading to the development of MDS and AML.
“Our discoveries may open new avenues in the study and in the treatment of MDS and AML,” Halene wrote to the News. “Future studies will help to deep characterize stress granule perturbations, pointing toward potential therapeutic targets.”
MDS and AML are most commonly observed in patients over 70 years of age.