Publications by authors named "Martina Sarchi"

Myeloid malignancies are a spectrum of clonal disorders driven by genetic alterations that cooperatively confer aberrant self-renewal and differentiation of hematopoietic stem and progenitor cells (HSPCs). Induced pluripotent stem cells (iPSCs) can be differentiated into HSPCs and have been widely explored for modeling hematological disorders and cell therapies. More recently, iPSCs models have been applied to study the origins and pathophysiology of myeloid malignancies, motivated by the appreciation for the differences in human oncogene function and the need for genetically defined models that recapitulate leukemia development.

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Splicing factor SF3B1 mutations are frequent somatic lesions in myeloid neoplasms that transform hematopoietic stem cells (HSCs) by inducing mis-splicing of target genes. However, the molecular and functional consequences of SF3B1 mutations in human HSCs and progenitors (HSPCs) remain unclear. Here, we identify the mis-splicing program in human HSPCs as a targetable vulnerability by precise gene editing of SF3B1 K700E mutations in primary CD34+ cells.

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Article Synopsis
  • Mutations in the SF3B1 gene are prevalent in various cancers and lead to incorrect RNA splicing, but there are currently no treatments to fix these issues.
  • Researchers discovered that the protein GPATCH8 is essential for the abnormal splicing caused by mutant SF3B1 and plays a key role in maintaining proper RNA processing.
  • By silencing GPATCH8, they found that it corrected many of the splicing errors and improved blood cell formation in models of SF3B1-mutant cancers, suggesting a potential therapeutic approach.
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Unlabelled: RNA splicing factor (SF) gene mutations are commonly observed in patients with myeloid malignancies. Here we showed that SRSF2- and U2AF1-mutant leukemias are preferentially sensitive to PARP inhibitors (PARPi), despite being proficient in homologous recombination repair. Instead, SF-mutant leukemias exhibited R-loop accumulation that elicited an R-loop-associated PARP1 response, rendering cells dependent on PARP1 activity for survival.

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Systematic studies of germ line genetic predisposition to myeloid neoplasms in adult patients are still limited. In this work, we performed germ line and somatic targeted sequencing in a cohort of adult patients with hypoplastic bone marrow (BM) to study germ line predisposition variants and their clinical correlates. The study population included 402 consecutive adult patients investigated for unexplained cytopenia and reduced age-adjusted BM cellularity.

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SF3B1 splicing factor mutations are near-universally found in myelodysplastic syndromes (MDS) with ring sideroblasts (RS), a clonal hematopoietic disorder characterized by abnormal erythroid cells with iron-loaded mitochondria. Despite this remarkably strong genotype-to-phenotype correlation, the mechanism by which mutant SF3B1 dysregulates iron metabolism to cause RS remains unclear due to an absence of physiological models of RS formation. Here, we report an induced pluripotent stem cell model of SF3B1-mutant MDS that for the first time recapitulates robust RS formation during in vitro erythroid differentiation.

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Article Synopsis
  • Clonal cytopenia of undetermined significance (CCUS) is linked to a higher risk of developing myeloid neoplasms, and a study of various patient cohorts revealed that about 30% of individuals with idiopathic cytopenia carry genetic mutations associated with CCUS.
  • The presence of clonal hematopoiesis (CH) was found in nearly 20% of non-anemic individuals and around 28% of those with unexplained anemia, with distinct mutation patterns indicating differing levels of disease progression risk.
  • Two main mutation clusters were identified, with one showing isolated DNMT3A mutations and the other characteristic combinatorial patterns, impacting both overall survival rates and the likelihood of progression to myeloid ne
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Somatic mutations in splicing factor genes frequently occur in myeloid neoplasms. While SF3B1 mutations are associated with myelodysplastic syndromes (MDS) with ring sideroblasts, SRSF2 mutations are found in different disease categories, including MDS, myeloproliferative neoplasms (MPN), myelodysplastic/myeloproliferative neoplasms (MDS/MPN), and acute myeloid leukemia (AML). To identify molecular determinants of this phenotypic heterogeneity, we explored molecular and clinical features of a prospective cohort of 279 SRSF2-mutated cases selected from a population of 2663 patients with myeloid neoplasms.

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