ABSTRACT
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.
ABSTRACT
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.
Subject(s)
B-Lymphocytes/immunology , Cellular Senescence , Gene Deletion , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Mutation , Neoplasms, Experimental/genetics , Phosphoproteins/genetics , RNA Splicing Factors/genetics , Receptors, Antigen, B-Cell/immunology , Adenine/analogs & derivatives , Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Agammaglobulinaemia Tyrosine Kinase/metabolism , Alternative Splicing , Animals , Antineoplastic Agents/pharmacology , Ataxia Telangiectasia Mutated Proteins/deficiency , Ataxia Telangiectasia Mutated Proteins/genetics , Ataxia Telangiectasia Mutated Proteins/metabolism , B-Lymphocytes/drug effects , B-Lymphocytes/metabolism , Cellular Senescence/drug effects , DNA Damage , Genetic Predisposition to Disease , Genomic Instability , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Knockout , Mice, Mutant Strains , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/immunology , Neoplasms, Experimental/metabolism , Phenotype , Phosphoproteins/metabolism , Piperidines , Protein Kinase Inhibitors/pharmacology , Pyrazoles/pharmacology , Pyrimidines/pharmacology , RNA Splicing Factors/metabolism , Receptors, Antigen, B-Cell/metabolism , Signal Transduction , Tumor Cells, CulturedABSTRACT
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.
