SF3B1 Mutations in Hematological Malignancies

Cilloni, Daniela; Itri, Federico; Bonuomo, Valentina; Petiti, Jessica

doi:10.3390/cancers14194927

Cited by 11 publications

(7 citation statements)

References 67 publications

(90 reference statements)

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“…Therefore, the function of SF3B1 is to assist in correctly localizing the spliceosome to the 3′ splice site. In Project ERIS, mutations in SF3B1 occurred in 2.6% (95% CI, 1.4 to 4.9) of patients with AML, with a median upfront variant allele frequency (VAF) of 46.1%, consistent with its known heterozygous presentation; additional aggregate analyses have confirmed SF3B1 mut frequencies of 2–5% in AML [ 21 ]. Mutations in SF3B1 frequently guide the spliceosome to an alternative 3′ splice site.…”

Section: Aberrations Of Spliceosome Genesmentioning

confidence: 99%

“…The abnormal splice site degrades a mitochondrial iron exporter, ABCB7 [ 23 ]. Reduction in functional ABCB7 leads to mitochondrial iron retention in erythroblasts, characteristically resulting in ringed sideroblasts, aberrant erythropoiesis, and a predilection for anemia [ 21 ]. Other mutations in SF3B1 create terminal blocks in erythroid maturation but without ringed sideroblasts [ 9 , 24 ].…”

Section: Aberrations Of Spliceosome Genesmentioning

confidence: 99%

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Secondary-Type Mutations in Acute Myeloid Leukemia: Updates from ELN 2022

Bouligny

Maher

Grant

2023

Cancers

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The characterization of the molecular landscape and the advent of targeted therapies have defined a new era in the prognostication and treatment of acute myeloid leukemia. Recent revisions in the European LeukemiaNet 2022 guidelines have refined the molecular, cytogenetic, and treatment-related boundaries between myelodysplastic neoplasms (MDS) and AML. This review details the molecular mechanisms and cellular pathways of myeloid maturation aberrancies contributing to dysplasia and leukemogenesis, focusing on recent molecular categories introduced in ELN 2022. We provide insights into novel and rational therapeutic combination strategies that exploit mechanisms of leukemogenesis, highlighting the underpinnings of splicing factors, the cohesin complex, and chromatin remodeling. Areas of interest for future research are summarized, and we emphasize approaches designed to advance existing treatment strategies.

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Section: Aberrations Of Spliceosome Genesmentioning

confidence: 99%

Section: Aberrations Of Spliceosome Genesmentioning

confidence: 99%

Secondary-Type Mutations in Acute Myeloid Leukemia: Updates from ELN 2022

Bouligny

Maher

Grant

2023

Cancers

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“…This process is catalyzed by the spliceosome, a highly dynamic ribonucleoprotein complex composed of several splicing factors and small nuclear RNAs. The dysregulation of splicing impairs cellular function and is associated with cancers and aging [2,3]. Pathogenic variants in genes encoding core spliceosomal components have been shown to disrupt the splicing process and lead to various monogenic disorders with defective tissue development [4,5].…”

Section: Introductionmentioning

confidence: 99%

Novel Genetic and Phenotypic Expansion in Ameliorated PUF60-Related Disorders

Baum,

Huang,

Vincent-Delorme

et al. 2024

IJMS

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Heterozygous variants in the Poly(U) Binding Splicing Factor 60kDa gene (PUF60) have been associated with Verheij syndrome, which has the key features of coloboma, short stature, skeletal abnormalities, developmental delay, palatal abnormalities, and congenital heart and kidney defects. Here, we report five novel patients from unrelated families with PUF60-related disorders exhibiting novel genetic and clinical findings with three truncating variants, one splice-site variant with likely reduced protein expression, and one missense variant. Protein modeling of the patient’s missense variant in the PUF60 AlphaFold structure revealed a loss of polar bonds to the surrounding residues. Neurodevelopmental disorders were present in all patients, with variability in speech, motor, cognitive, social-emotional and behavioral features. Novel phenotypic expansions included movement disorders as well as immunological findings with recurrent respiratory, urinary and ear infections, atopic diseases, and skin abnormalities. We discuss the role of PUF60 in immunity with and without infection based on recent organismic and cellular studies. As our five patients showed less-severe phenotypes than classical Verheij syndrome, particularly with the absence of key features such as coloboma or palatal abnormalities, we propose a reclassification as PUF60-related neurodevelopmental disorders with multi-system involvement. These findings will aid in the genetic counseling of patients and families.

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“…Splicing Factor 3b Subunit 1 (SF3B1) is the largest subunit of the splicing factor 3b (SF3b) protein complex and is a constituent of U2 small nuclear ribonucleoprotein (U2snRNP) [8]. Mutations in SF3B1 are the most frequent and relevant spliceosome mutations in hematological diseases, including myelodysplastic syndromes [9]. SF3B1 mutations cause aberrant splicing and activation of inflammatory immune signaling in myelodysplastic syndromes [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of SF3B1 improves the immune microenvironment through pyroptosis and synergizes with αPDL1 in ovarian cancer

Wang,

Liu,

Xiao

et al. 2023

Cell Death Dis

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Ovarian cancer is resistant to immune checkpoint blockade (ICB) treatment. Combination of targeted therapy and immunotherapy is a promising strategy for ovarian cancer treatment benefit from an improved immune microenvironment. In this study, Clinical Proteomic Tumor Analysis Consortium (CPTAC) and The Cancer Genome Atlas (TCGA) cohorts were used to screen prognosis and cytotoxic lymphocyte infiltration-associated genes in upregulated genes of ovarian cancer, tissue microarrays were built for further verification. In vitro experiments and mouse (C57/BL6) ovarian tumor (ID8) models were built to evaluate the synergistic effect of the combination of SF3B1 inhibitor and PD-L1 antibody in the treatment of ovarian cancer. The results show that SF3B1 is shown to be overexpressed and related to low cytotoxic immune cell infiltration in ovarian cancer. Inhibition of SF3B1 induces pyroptosis in ovarian cancer cells and releases mitochondrial DNA (mtDNA), which is englobed by macrophages and subsequently activates them (polarization to M1). Moreover, pladienolide B increases cytotoxic immune cell infiltration in the ID8 mouse model as a SF3B1 inhibitor and increases the expression of PD-L1 which can enhance the antitumor effect of αPDL1 in ovarian cancer. The data suggests that inhibition of SF3B1 improves the immune microenvironment of ovarian cancer and synergizes ICB immunotherapy, which provides preclinical evidence for the combination of SF3B1 inhibitor and ICB to ovarian cancer treatment.

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SF3B1 Mutations in Hematological Malignancies

Cited by 11 publications

References 67 publications

Secondary-Type Mutations in Acute Myeloid Leukemia: Updates from ELN 2022

Secondary-Type Mutations in Acute Myeloid Leukemia: Updates from ELN 2022

Novel Genetic and Phenotypic Expansion in Ameliorated PUF60-Related Disorders

Inhibition of SF3B1 improves the immune microenvironment through pyroptosis and synergizes with αPDL1 in ovarian cancer

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