More than 80% of patients with the refractory anemia with ring sideroblasts subtype of myelodysplastic syndrome (MDS) have mutations in Splicing Factor 3B, Subunit 1 (SF3B1). We generated a ...conditional knockin mouse model of the most common SF3B1 mutation, Sf3b1(K700E). Sf3b1(K700E) mice develop macrocytic anemia due to a terminal erythroid maturation defect, erythroid dysplasia, and long-term hematopoietic stem cell (LT-HSC) expansion. Sf3b1(K700E) myeloid progenitors and SF3B1-mutant MDS patient samples demonstrate aberrant 3' splice-site selection associated with increased nonsense-mediated decay. Tet2 loss cooperates with Sf3b1(K700E) to cause a more severe erythroid and LT-HSC phenotype. Furthermore, the spliceosome modulator, E7017, selectively kills SF3B1(K700E)-expressing cells. Thus, SF3B1(K700E) expression reflects the phenotype of the mutation in MDS and may be a therapeutic target in MDS.
SF3B1 is recurrently mutated in chronic lymphocytic leukemia (CLL), but its role in the pathogenesis of CLL remains elusive. Here, we show that conditional expression of Sf3b1-K700E mutation in mouse ...B cells disrupts pre-mRNA splicing, alters cell development, and induces a state of cellular senescence. Combination with Atm deletion leads to the overcoming of cellular senescence and the development of CLL-like disease in elderly mice. These CLL-like cells show genome instability and dysregulation of multiple CLL-associated cellular processes, including deregulated B cell receptor signaling, which we also identified in human CLL cases. Notably, human CLLs harboring SF3B1 mutations exhibit altered response to BTK inhibition. Our murine model of CLL thus provides insights into human CLL disease mechanisms and treatment.
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•Sf3b1-K700E mutation impairs 3′ splice site selection and induces cellular senescence•Sf3b1-K700E mutation in combination with Atm deletion causes CLL•CLL cells show genome instability and dysregulated BCR signaling•Human CLL cells with SF3B1 mutations show dysregulation of BCR signaling
Yin et al. show that Sf3b1-K700E mutation in mouse B cells induces cellular senescence, but deletion of Atm overcomes senescence and leads to the development of CLL-like disease. Both human and mouse CLL harboring mutant SF3B1 exhibit deregulated B cell receptor signaling and increased sensitivity to ibrutinib.
There is an increasing prevalence of cancer in Africa with approximately 80% of cancers diagnosed at an advanced stage. High out-of-pocket healthcare costs and overstretched health systems lead to ...heavy reliance on informal carers for cancer care. This study aims to explore the roles and experiences of informal carers including the impact of cancer care on individuals and communities and support available for carers. We carried out a systematic review following PRISMA reporting guidelines and used critical interpretative synthesis to identify themes and develop an informal carers' experience framework. We searched nine databases and screened 8,123 articles from which 31 studies were included in the review. Most studies were from Sub-Saharan Africa (29/31, 94%), particularly Uganda (9, 29%). Carers were mostly women, aged 30-40 years, and siblings, spouses, or children. Caring roles included care coordination, fundraising, and emotional support. Caring was time-consuming with some carers reporting 121 hours/week of caring, associated with the inability to pursue paid work and depression. Four themes demonstrated carers' experiences: 1) intrapersonal factors: strong sense of familial obligation, and grappling with gender roles, 2) interpersonal factors: impact of a cancer diagnosis on households, changing social and sexual relationships, 3) community factors: navigating cultural norms on nature and location of care, and 4) health system influences: barriers to accessing healthcare services, and tensions between traditional and biomedical medicine. These themes aligned with Bronfenbrenner's social ecological model which aided our development of a framework for understanding informal carers' experiences'. Our review highlights multifaceted roles and experiences of informal carers in Africa, amidst cultural and community impacts. Carers experience a strong obligation and willingly undertake the role of carer, but at the expense of their social, economic, and psychological wellbeing. Support for carers, including flexible working hours/ carers' allowance, should be incorporated as part of universal health coverage.
More than 80% of patients with the refractory anemia with ring sideroblasts subtype of myelodysplastic syndrome (MDS) have mutations in Splicing Factor 3B, Subunit 1 (SF3B1). We generated a ...conditional knockin mouse model of the most common SF3B1 mutation, Sf3b1 K700E. Sf3b1 K700E mice develop macrocytic anemia due to a terminal erythroid maturation defect, erythroid dysplasia, and long-term hematopoietic stem cell (LT-HSC) expansion. Sf3b1 K700E myeloid progenitors and SF3B1-mutant MDS patient samples demonstrate aberrant 3' splice-site selection associated with increased nonsense-mediated decay. Tet2 loss cooperates with Sf3b1 K700E to cause a more severe erythroid and LT-HSC phenotype. Furthermore, the spliceosome modulator, E7017, selectively kills SF3B1K700E-expressing cells. Thus, SF3B1K700E expression reflects the phenotype of the mutation in MDS and may be a therapeutic target in MDS.
Over 80% of patients with the refractory anemia with ring sideroblasts subtype of myelodysplastic syndrome (MDS) have mutations in Splicing Factor 3B, Subunit 1 (
SF3B1
). We generated a conditional ...knock-in mouse model of the most common
SF3B1
mutation,
Sf3b1
K700E
.
Sf3b1
K700E
mice develop macrocytic anemia due to a terminal erythroid maturation defect, erythroid dysplasia, and long-term hematopoietic stem cell (LT-HSC) expansion.
Sf3b1
K700E
myeloid progenitors and
SF3B1
-mutant MDS patient samples demonstrate aberrant 3’ splice-site selection associated with increased nonsense-mediated decay.
Tet2
loss cooperates with
Sf3b1
K700E
to cause a more severe erythroid and LT-HSC phenotype. Furthermore, the spliceosome modulator, E7017, selectively kills SF3B1
K700E
-expressing cells. Thus, SF3B1
K700E
expression reflects the phenotype of the mutation in MDS and may be a therapeutic target in MDS.
Obeng et al. generate knockin mice with SF3B1
K700E
, a prevalent mutation in myelodysplastic syndrome (MDS).
Sf3b1
+/K700E
mice display characteristics of MDS. Mouse and human MDS cells expressing SF3B1
K700E
exhibit aberrant 3’ splice site selection, and SF3B1
K700E
sensitizes cells to a spliceosome modulator.
More than 80% of patients with the refractory anemia with ring sideroblasts subtype of myelodysplastic syndrome (MDS) have mutations in Splicing Factor 3B, Subunit 1 (SF3B1). We generated a ...conditional knockin mouse model of the most common SF3B1 mutation, Sf3b1K700E. Sf3b1K700E mice develop macrocytic anemia due to a terminal erythroid maturation defect, erythroid dysplasia, and long-term hematopoietic stem cell (LT-HSC) expansion. Sf3b1K700E myeloid progenitors and SF3B1-mutant MDS patient samples demonstrate aberrant 3′ splice-site selection associated with increased nonsense-mediated decay. Tet2 loss cooperates with Sf3b1K700E to cause a more severe erythroid and LT-HSC phenotype. Furthermore, the spliceosome modulator, E7017, selectively kills SF3B1K700E-expressing cells. Thus, SF3B1K700E expression reflects the phenotype of the mutation in MDS and may be a therapeutic target in MDS.
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•Sf3b1+/K700E mice develop a progressive macrocytic anemia and myelodysplasia•Mutant SF3B1 causes aberrant 3′ splice-site selection•Sf3b1+/K700E and Tet2 loss cause an earlier onset of MDS characteristics•Spliceosome modulators selectively kill cells expressing SF3B1K700E
Obeng et al. generate knockin mice with Sf3b1K700E, a prevalent mutation in myelodysplastic syndrome (MDS). Sf3b1+/K700E mice display characteristics of MDS. Mouse and human MDS cells expressing SF3B1K700E exhibit aberrant 3′ splice-site selection, and SF3B1K700E sensitizes cells to a spliceosome modulator.
Abstract only
The enzyme thimet oligopeptidase (TOP) is present in a wide variety of cell types and hydrolyzes many peptides of physiological importance in neuroendocrine pathways. TOP has been ...identified in prostate cancer cells, and its activity is increased by androgens in androgen‐responsive cells. Using the androgen‐sensitive cell line DU145‐AR, we have found that TOP levels and activity were significantly increased after 24 hours incubation with either dihydrotestosterone or estradiol. TOP was found both intracellularly and in the medium. These increases were not observed with an androgen‐insensitive line (DU145‐T). TOP works in concert with the peptidase prolyl endopeptidase (PEP) in breakdown of gonadotropin‐releasing hormone (GnRH), a peptide known to influence growth of prostate cells. We have identified PEP in DU145‐AR cells and seen an increase in PEP levels with androgen treatment. Furthermore, immunocytochemistry revealed that TOP was more clearly localized to nuclei at high levels of estradiol, compared to its distribution between cytoplasm and nucleus in the absence of steroid or at low levels of estradiol. These results suggest that peptidases, especially those involved in GnRH metabolism, may be involved in regulation of growth of prostate cancer cells and, hence, be targets for cancer therapy.
Mutations in SF3B1, which encodes a spliceosome component, are associated with poor outcome in chronic lymphocytic leukemia (CLL), but how these contribute to CLL progression remains poorly ...understood. We undertook a transcriptomic characterization of primary human CLL cells to identify transcripts and pathways affected by SF3B1 mutation. Splicing alterations, identified in the analysis of bulk cells, were confirmed in single SF3B1-mutated CLL cells and also found in cell lines ectopically expressing mutant SF3B1. SF3B1 mutation was found to dysregulate multiple cellular functions including DNA damage response, telomere maintenance, and Notch signaling (mediated through KLF8 upregulation, increased TERC and TERT expression, or altered splicing of DVL2 transcript, respectively). SF3B1 mutation leads to diverse changes in CLL-related pathways.
•SF3B1 mutation causes alternative splicing in cell lines and primary CLL cells•SF3B1 mutation-associated splice variants are enriched for 3′ splice sites•SF3B1 mutation induces RNA changes affecting multiple CLL-associated pathways•SF3B1 mutation modulates Notch signaling through an RNA splice variant of DVL2
Wang et al. perform transcriptomic characterization of bulk or single primary human chronic lymphocytic leukemia cells harboring SF3B1 mutations, identifying several dysregulated cancer-related pathways resulting from altered expression of KLF8, TERC, or TERT or altered splicing of DVL2 mRNA.
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