Authors
He Tian Tony Chen, Pratik Joshi, Severine Cathelin, Soheil Jahangiri Tazehkand, Saeer A Adeel, Joshua Xu, Emily Tsao, Yulin Mo, David Kealy, Adam Dowle, Zaldy Balde, Marry Xuan, Dylan Gowlett-Park, Katarina Czibere, Alexandra Misura, Olga Bigun, Renato Sasso, August Lin, Noor Kundu, Dianne Chadwick, Sila Usta, Tina Khazaee, Signy Chow, Hubert Tsui, Mark D Minden, Andrew N Holding, Katherine S Bridge, Gang Zheng, Kristin Hope
Published in
Blood. Jun 18, 2026. Epub Jun 18, 2026.
Abstract
Myelodysplastic neoplasms (MDS) feature hematopoietic deficits driven in part by transcript splicing abnormalities. Thus far, such disease-driving transcripts have been identified in association with specific splicing factor mutations. However, conserved aberrant splicing-derived transcripts that drive MDS independently of mutational status remain poorly studied despite representing global therapeutic targets. Here, we characterize an MDS-associated MBD1 isoform (MBD1-L) as a novel member of this class of transcripts. Rather than originating from a mutant splicing factor, the abnormal production of MBD1-L is driven by reduced WTAP expression in MDS. Overexpression of MBD1-L in healthy human HSPCs recapitulates archetypal MDS defects, including reduced terminal GLYA+ erythroid differentiation, suppressed cell cycling and impaired in vivo reconstitution capacity during increased hematopoietic demand in xenotransplantation assays. An integrated multiomics approach assessing DNA binding of MBD1 isoforms, and resulting changes in chromatin accessibility, histone mark deposition and transcriptional changes, revealed that these defects arise from an isoform-specific switching of MBD1's binding behavior. The MBD1-L isoform refocuses MBD1-L's heterochromatin-promoting activity from methylated to unmethylated CpGs and thus enacting broad downregulation of CpG-rich promoters as well as secondary epigenetic effects mediated by its downstream target BCOR. Remarkably, we also find that directly reversing abnormal MBD1 splicing across a broad range of primary human MDS samples using nanoparticle-encapsulated ASOs enhances in vitro erythroid differentiation, supporting the utility of RNA therapies for MDS treatment. Thus, our findings demonstrate MBD1-L to be a global, disease-driving splice variant across MDS, and illustrate the potential for RNA-based therapies in the broad treatment of MDS.
PMID:
42322117
Bibliographic data and abstract were imported from PubMed on 20 Jun 2026.
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