ABSTRACT
Haematopoietic stem and progenitor cells (HSPCs) are defined as unspecialized cells that give rise to more differentiated cells. In a similar way, leukaemic stem and progenitor cells (LSPCs) are defined as unspecialized leukaemic cells, which can give rise to more differentiated cells. Leukaemic cells carry leukaemic mutations/variants and have clear differentiation abnormalities. Pre-leukaemic HSPCs (PreL-HSPCs) carry pre-leukaemic mutations/variants (pLMs) and are capable of producing mature functional cells, which will carry the same variants. Under the roof of LSPCs, one can find a broad range of cell types genetic and disease phenotypes. Present-day knowledge suggests that this phenotypic heterogeneity is the result of interactions between the cell of origin, the genetic background and the microenvironment background. The combination of these attributes will define the LSPC phenotype, frequency, differentiation capacity and evolutionary trajectory. Importantly, as LSPCs are leukaemia-initiating cells that sustain clinical remission and are the source of relapse, an improved understanding of LSPCs phenotype would offer better clinical opportunities for the treatment and hopefully prevention of human leukaemia. The current review will focus on LSPCs attributes in the context of human haematologic malignancies.
Subject(s)
Hematopoietic Stem Cells/pathology , Leukemia/pathology , Preleukemia/pathology , Biomarkers, Tumor , Bone Marrow/pathology , Drug Resistance, Neoplasm , Gene Expression Regulation, Neoplastic , Genetic Variation , Hematopoiesis , Humans , Leukemia/genetics , Leukemia/metabolism , Mutation , Phenotype , Preleukemia/genetics , Preleukemia/metabolism , Tumor MicroenvironmentABSTRACT
Acute myeloid leukemia (AML) is characterized by accumulation of myeloid cells in the bone marrow because of impaired differentiation and proliferation, resulting in hematopoietic insufficiency. NPM1 is one of the most commonly mutated genes in AML, present in 20-30% of cases. Mutations in NPM1 represent a distinct entity in the World Health Organization (WHO) classification and commonly indicate a better risk prognosis. In this review, we discuss the many functions of NPM1, the consequence of mutations in NPM1 and possible mechanisms through which mutations lead to leukemogenesis. We also discuss clinical consequences of mutations, associated gene expression patterns and the role of NPM1 mutations in informing prognosis and therapeutic decisions and predicting relapse in AML.
Subject(s)
Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/genetics , Mutation , Nuclear Proteins/genetics , Biomarkers, Tumor , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/metabolism , Clinical Decision-Making , Epistasis, Genetic , Gene Expression Regulation, Leukemic , Gene Frequency , Humans , Leukemia, Myeloid, Acute/therapy , Neoplasm, Residual/diagnosis , Neoplasm, Residual/genetics , Neoplasm, Residual/metabolism , Nuclear Proteins/chemistry , Nuclear Proteins/metabolism , Nucleophosmin , Prognosis , Protein Binding , Protein Interaction Domains and Motifs , Protein Processing, Post-Translational , RecurrenceABSTRACT
BACKGROUND: Prolidase deficiency is a complex disease characterized by various skin manifestations accompanied by mental retardation, facial dysmorphism and susceptibility to pyogenic infections. METHODS: We assessed a patient presenting a peculiar phenotype combining manifestations of prolidase deficiency with features typical of hyper-IgE syndrome. Mutation analysis was performed using direct PCR amplification and PCR restriction fragment length polymorphism analysis. RESULTS: We identified a novel homozygous recessive mutation in the PEPD gene, which was found to segregate in the family of the patient with the disease and was not found in a panel of DNA samples representative of all major Druze families living in northern Israel. DISCUSSION: Our results suggest that prolidase deficiency associated with hyper-IgE syndrome, a rare disorder, can be caused by mutations in PEPD.
