Photo courtesy of the University
of California San Diego
Researchers say they have identified RNA-based biomarkers that distinguish normal, aged hematopoietic stem and progenitor cells (HSPCs) from leukemia stem cells (LSCs) associated with secondary acute myeloid leukemia (sAML).
The team believes their discovery may provide a new way to predict leukemic relapse and identify targets for drug development.
Catriona Jamieson, MD, PhD, of the University of California San Diego in La Jolla, and her colleagues described the discovery in Cell Stem Cell.
The researchers noted that age-related hematopoietic stem cell exhaustion and myeloid-lineage skewing promote the transformation of hematopoietic progenitors into therapy-resistant LSCs in sAML. However, the contribution of RNA processing alterations to HSPC aging and LSC generation remains unclear.
With this study, Dr Jamieson and her colleagues discovered RNA splice isoform expression patterns that distinguished normal, aged HSPCs from sAML LSCs.
The team said the aged HSPCs displayed pro-apoptotic BCL2 splice isoform switching, while sAML LSCs favored pro-survival expression of BCL2L1 (BCL-XL).
“These splicing signatures could potentially be used as clinical biomarkers to detect blood stem cells that show signs of early aging or leukemia and to monitor patient responses to treatment,” said study author Leslie Crews, PhD, of the University of California San Diego.
“By being able to distinguish benign from malignant aging based on distinctive RNA splicing patterns, we can develop therapeutic strategies that selectively target leukemia stem cells while sparing normal hematopoietic stem cells,” Dr Jamieson added.
In fact, she and her colleagues were able to show that treatment with a pharmacologic splicing modulator known as 17S-FD-895 could eradicate sAML LSCs while sparing normal HSPCs. The compound reversed pro-survival splice isoform switching and impaired LSC maintenance.
“Our findings show that RNA splicing is a unique therapeutic vulnerability for secondary AML,” Dr Jamieson said. “RNA-splicing-targeted therapies may be a potent and selective way to clear leukemia stem cells and prevent relapse.”
