New Insights Into MDS and AML: Clonal Analysis Reveals Shared Splicing Neoantigens and Therapeutic Targets

The here-identified shared splicing neoantigens and key molecular pathways could inform future therapies for myelodysplastic syndromes (MDS) and myelodysplasia-related (MR)–acute myeloid leukemia (AML). Next to the potential clinical impact, these findings underscore the potential of single-cell analyses in the unbiased unraveling of disease mechanisms.

MDS are chronic myeloid malignancies that carry a genetic risk of progressing to MR-AML, characterized by clonal hematopoiesis and dysfunctional hematopoietic stem cells and progenitor cells (HSCPs). Although therapy with hypomethylating agents (HMAs) provides clinical benefits for some patients, the efficacy of HMAs remains limited, particularly in high-risk cases.

To better understand therapeutic responses and leukemic transformation, Nathan Salomonis, PhD, Cincinnati Children’s Hospital Medical Center, Ohio, and colleagues used advanced single-cell RNA sequencing, combining short- and long-read technologies to profile bone marrow HSCPs from young to old healthy donors and participants with MDS or MDS with secondary AML with and without HMA treatment.¹

Aging significantly altered the most primitive HSCPs (early lymphoid, monocytic, and dendritic progenitors) and was linked to increased interferon signaling and broad splicing disruptions in these cells, contributing to their functional decline. In HSCPs from MDS biopsies, these changes were compounded by the downregulation of inflammatory, glucocorticoid, and cytokine signaling pathways and splicing regulators in quiescent HSCs. HMA treatment in the same participants only partially corrected these gene expression and splicing abnormalities, and distinct malignant clones emerged during therapy and disease progression, highlighting the persistence of resistant subpopulations. Using long-read sequencing on HSCPs, the researchers pinpointed hundreds of splicing neoantigens, including several linked to common mutations in splicing factors, such as SRSF2, that could prove to be useful immunotargets in the future.

“The identified neoantigens have the potential to act as biomarkers for tailoring individualized treatment approaches or as targets for developing new therapies to overcome resistance to HMAs,” concluded Salomonis. In addition, the findings emphasize the importance of age-matched controls in studies of MDS because age-related changes in HSC biology may confound the interpretation of disease-specific alterations.

REFERENCE

Salomonis S, Li G, Oliverio A, et al. Clonal dissection of MDS and secondary AML resolves shared splicing neoantigens and mechanistic underpinnings of hypomethylating agent therapeutic response. Abstract #1810. Presented at the ASH Annual Meeting; December7-10, 2024; San Diego, California.