Abstract
Telomere erosion–induced DNA damage alters myeloid progenitor differentiation and induces MDS.
Major finding: Telomere erosion–induced DNA damage alters myeloid progenitor differentiation and induces MDS.
Mechanism: Telomere dysfunction promotes aberrant RNA splicing via repression of RNA splicing components.
Impact: Persistent DNA damage causes aberrant myeloid differentiation and contributes to high-grade MDS.
Myelodysplastic syndrome (MDS) represents a group of hematopoietic disorders defined by impaired myeloid differentiation of committed progenitor cells. MDS is associated with advanced age, DNA damage, and shortened telomeres; however, it is unknown if persistent DNA damage can directly instigate MDS. Colla, Ong, and colleagues used a murine model of progressive telomere erosion to demonstrate that telomere dysfunction and the resulting DNA damage induced bone marrow dysplasia, accumulation of DNA damage in common myeloid progenitors (CMP), and skewed myeloid–erythroid differentiation, recapitulating hallmark features of human MDS. Telomerase reactivation reversed DNA damage and restored normal myeloid and erythroid populations. Bone marrow transfer of telomere-eroded hematopoietic stem cells demonstrated that telomere dysfunction impaired CMP differentiation via cell-intrinsic DNA damage signaling, in particular activation of ataxia telangiectasia and RAD3-related (ATR), which has a known role in telomere dysfunction and was phosphorylated in patients with high-risk MDS. Inhibition of ATR improved erythroid differentiation of telomere-eroded CMPs. Mechanistically, telomere dysfunction repressed the expression of genes encoding RNA splicing and processing components specifically in the CMP population, which was rescued by telomerase reactivation or inhibition of ATR. RNA sequencing analysis revealed aberrant splicing of transcripts involved in the DNA damage response, maintenance of genome stability, chromatin remodeling, and histone modification pathways in telomere-dysfunctional CMPs. Consistent with these findings, inhibition of spliceosome assembly or haploinsufficiency for serine/arginine-rich splicing factor 2 (SRSF2) impaired CMP differentiation and resulted in multilineage dysplasia in mice. In addition, SRSF2-haploinsufficient CMP cells and SRSF2-mutant cells isolated from patients with MDS exhibited aberrant splicing events in a similar subset of genes involved in telomere maintenance and DNA repair. Together, these data suggest a strong connection between telomere shortening, DNA damage, and RNA splicing in the regulation of myeloid differentiation and induction of the MDS phenotype.