7 research outputs found
ILF2-YB1 INTERACTION MODULATES RNA SPLICING TO INDUCE RESISTANCE TO DNA-DAMAGING AGENTS IN 1Q21-AMPLIFIED MULTIPLE MYELOMA
A Mouse Model of Telomere Dysfunction Recapitulates Hallmark Features of Human Myelodysplastic Syndrome
Stem cell architecture drives myelodysplastic syndrome progression and predicts response to venetoclax-based therapy
Myelodysplastic syndromes (MDS) are heterogeneous neoplastic disorders of hematopoietic stem cells (HSCs). The current standard of care for patients with MDS is hypomethylating agent (HMA)-based therapy; however, almost 50% of MDS patients fail HMA therapy and progress to acute myeloid leukemia, facing a dismal prognosis due to lack of approved second-line treatment options. As cancer stem cells are the seeds of disease progression, we investigated the biological properties of the MDS HSCs that drive disease evolution, seeking to uncover vulnerabilities that could be therapeutically exploited. Through integrative molecular profiling of HSCs and progenitor cells in large patient cohorts, we found that MDS HSCs in two distinct differentiation states are maintained throughout the clinical course of the disease, and expand at progression, depending on recurrent activation of the anti-apoptotic regulator BCL-2 or nuclear factor-kappa B-mediated survival pathways. Pharmacologically inhibiting these pathways depleted MDS HSCs and reduced tumor burden in experimental systems. Further, patients with MDS who progressed after failure to frontline HMA therapy and whose HSCs upregulated BCL-2 achieved improved clinical responses to venetoclax-based therapy in the clinical setting. Overall, our study uncovers that HSC architectures in MDS are potential predictive biomarkers to guide second-line treatments after HMA failure. These findings warrant further investigation of HSC-specific survival pathways to identify new therapeutic targets of clinical potential in MDS
Author Correction: Stem cell architecture drives myelodysplastic syndrome progression and predicts response to venetoclax-based therapy (Nature Medicine, (2022), 28, 3, (557-567), 10.1038/s41591-022-01696-4)
In the version of this article initially published, the name of the Edward P. Evans Foundation was shown incorrectly in the first sentence of the Acknowledgements. The name has been corrected in the HTML and PDF versions of the paper
Telomere Dysfunction Drives Aberrant Hematopoietic Differentiation and Myelodysplastic Syndrome
SummaryMyelodysplastic syndrome (MDS) risk correlates with advancing age, therapy-induced DNA damage, and/or shorter telomeres, but whether telomere erosion directly induces MDS is unknown. Here, we provide the genetic evidence that telomere dysfunction-induced DNA damage drives classical MDS phenotypes and alters common myeloid progenitor (CMP) differentiation by repressing the expression of mRNA splicing/processing genes, including SRSF2. RNA-seq analyses of telomere dysfunctional CMP identified aberrantly spliced transcripts linked to pathways relevant to MDS pathogenesis such as genome stability, DNA repair, chromatin remodeling, and histone modification, which are also enriched in mouse CMP haploinsufficient for SRSF2 and in CD34+ CMML patient cells harboring SRSF2 mutation. Together, our studies establish an intimate link across telomere biology, aberrant RNA splicing, and myeloid progenitor differentiation