Summary Some cancers originate from a single mutation event in a single cell. Blood cancers known as myeloproliferative neoplasms (MPNs) are thought to originate when a driver mutation is acquired by a hematopoietic stem cell (HSC). However, when the mutation first occurs in individuals and how it affects the behavior of HSCs in their native context is not known. Here we quantified the effect of the JAK2 -V617F mutation on the self-renewal and differentiation dynamics of HSCs in treatment-naive individuals with MPNs and reconstructed lineage histories of individual HSCs using somatic mutation patterns. We found that JAK2- V617F mutations occurred in a single HSC several decades before MPN diagnosis—at age 9 ± 2 years in a 34-year-old individual and at age 19 ± 3 years in a 63-year-old individual—and found that mutant HSCs have a selective advantage in both individuals. These results highlight the potential of harnessing somatic mutations to reconstruct cancer lineages.

Highlights d High-throughput screening identifies specific small-molecule PAPD5 inhibitor BCH001 d BCH001 restores telomere length in iPSCs from patients with dyskeratosis congenita d Repurposed HBsAg suppressors, dihydroquinolizinones, increase TERC in stem cells d Oral PAPD5 inhibitors restore TERC and telomeres in human HSPCs in vivo

Allogeneic hematopoietic stem cell transplantation is the only potentially curative treatment for patients with myelodysplastic syndrome (MDS), but long-term survival is limited by the risk of transplant-related complications. Short telomere length, mediated by inherited or acquired factors, impairs cellular response to genotoxic and replicative stress and could identify patients at higher risk for toxicity after transplantation. We measured relative telomere length in pre-transplant recipient blood samples in 1514 MDS patients and evaluated the association of telomere length with MDS disease characteristics and transplantation outcomes. Shorter telomere length was significantly associated with older age, male sex, somatic mutations that impair the DNA damage response, and more severe pre-transplant cytopenias, but not with bone marrow blast count, MDS treatment history, or history of prior cancer therapy. Among 1267 patients ≥40 years old, telomere length in the shortest quartile was associated with inferior survival (p<0.001) due to a high risk of non-relapse mortality (p=0.001) after adjusting for significant clinical and genetic variables. The adverse impact of shorter telomeres on NRM was independent of recipient comorbidities and was observed selectively among patients receiving more intensive conditioning, including myeloablative regimens and higher-dose melphalan-based reduced-intensity regimens. The effect of shorter telomeres on NRM was prominent among patients who developed severe acute graft-versus-host disease, suggesting that short telomere length may limit regenerative potential of mucosal tissues after acute injury. MDS patients with shorter telomere length, who have inferior survival driven by excess toxicity, could be considered for strategies focused on minimizing toxic effects of transplantation.

Germline pathogenic TERT variants are associated with short telomeres and an increased risk of developing myelodysplastic syndrome (MDS) among patients with a telomere biology disorder. We identified TERT rare variants in 41 of 1514 MDS patients (2.7%) without a clinical diagnosis of a telomere biology disorder who underwent allogeneic transplantation. Patients with a TERT rare variant had shorter telomere length (p<0.001) and younger age at MDS diagnosis (52 vs. 59 years, p=0.03) than patients without a TERT rare variant. In multivariable models, TERT rare variants were associated with inferior overall survival (p=0.034) driven by an increased incidence of non-relapse mortality (NRM) (p=0.015). Death from a non-infectious pulmonary cause was more frequent among patients with a TERT rare variant. The majority of variants were missense substitutions and classified as variants of unknown significance (VUS). Therefore, we cloned all rare missense variants and quantified their impact on telomere elongation in a cell-based assay. We found that 90 percent of TERT rare variants had severe or intermediate impairment in their capacity to elongate telomeres. Using a homology model of human TERT bound to the shelterin protein TPP1, we inferred that TERT rare variants disrupt domain-specific functions, including catalysis, protein-RNA interactions, and recruitment to telomeres. Our results indicate that the contribution of TERT rare variants to MDS pathogenesis and NRM risk is underrecognized. Routine screening for TERT rare variants in MDS patients regardless of age or clinical suspicion may identify clinically inapparent telomere biology disorders and improve transplant outcomes through risk-adapted approaches.

Literature is scarce regarding the use of clopidogrel during pregnancy and the potential hazard to maternal and fetal health. We report a 33-year-old female, who presented to our clinic at 40 weeks gestation with a history of multiple prior ischemic strokes and transient ischemic attacks. The patient was placed on clopidogrel for secondary stroke prophylaxis prior to conception and maintained therapy throughout pregnancy without interruption or complication. Clopidogrel was discontinued 7 days prior to induction of labor, and a healthy baby was vaginally delivered without bleeding complications or congenital anomalies. Clopidogrel was restarted 12 hours postpartum without an incident. To our knowledge, this is the first report of clopidogrel use in pregnancy for secondary stroke prophylaxis. We also provide a current review of the literature of the use of clopidogrel in pregnancy. Based on the limited data available, clopidogrel use in pregnancy has not demonstrated significant toxicity to either the mother or the newborn. However, additional studies are needed to further assess the efficacy and safety of this medication in this patient population.