Posted: Friday, March 26, 2021
Mutations in the NPM1 gene are present in many patients with acute myeloid leukemia (AML). Using advanced RNA sequencing, Benjamin Haibe-Kains, PhD, of the Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, and colleagues identified two unique subtypes of this prominent aberration. The results, which were published in Nature Communications, suggest that one of these subtypes may be effectively treated with drugs already in use.
The investigators used a custom-built advanced computational model to analyze RNA from leukemic cells. Two subtypes of NPM1-mutated AML were identified based on gene expression: primitive and committed. The primitive subtype seemed to be significantly enriched for stem cells. In contrast, the committed subtype was found to be enriched for gene expression associated with myeloid and hematopoietic differentiation.
“Once we were able to identify the pattern of each subtype, we analyzed existing pharmacogenomics data to narrow a list of drugs that might be able to target one subtype or the other,” explained Dr. Haibe-Kains in a UHN press release. “We found two drugs that seemed to effectively target the primitive subtype in the lab, with potential to move to clinical trials in the future.”
The primitive subtype seemed to be more sensitive to sorafenib and sunitinib compared with committed subtype samples. The target genes of both multikinase inhibitors appeared to be enriched in the primitive subtype. However, the committed subtype was found to be enriched in genes and pathways that are implicated in drug resistance.
“The transcriptomic, assay for transposase-accessible chromatin with sequencing and immunophenotypic profiles identified in this study have implications in predicting response to therapy and potential changes in treatment decisions,” the investigators concluded.
Disclosure: For full disclosures of the study authors, visit nature.com.