| 1. |
- Attema, Joanne, et al.
(författare)
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Hematopoietic stem cell ageing is uncoupled from p16 INK4A-mediated senescence
- 2009
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Ingår i: Oncogene. - : Nature Publishing Group. - 0950-9232 .- 1476-5594. ; 28:22, s. 2238-2243
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Tidskriftsartikel (refereegranskat)abstract
- Somatic stem cells are ultimately responsible for mediating appropriate organ homeostasis and have therefore been proposed to represent a cellular origin of the ageing process-a state often characterized by inappropriate homeostasis. Specifically, it has been suggested that ageing stem cells might succumb to replicative senescence by a mechanism involving the cyclin-dependent kinase inhibitor p16(INK4A). Here, we tested multiple functional and molecular parameters indicative of p16(INK4A) activity in primary aged murine hematopoietic stem cells (HSCs). We found no evidence that replicative senescence accompanies stem cell ageing in vivo, and in line with p16(INK4A) being a critical determinant of such processes, most aged HSCs (>99%) failed to express p16(INK4A) at the mRNA level. Moreover, whereas loss of epigenetically guided repression of the INK4A/ARF locus accompanied replicative senescent murine embryonic fibroblasts, such repression was maintained in aged stem cells. Taken together, these studies indicate that increased senescence as mediated by the p16(INK4A) tumor suppressor has only a minor function as an intrinsic regulator of steady-state HSC ageing in vivo.
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| 2. |
- Lilljebjörn, Henrik, et al.
(författare)
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Identification of ETV6-RUNX1-like and DUX4-rearranged subtypes in paediatric B-cell precursor acute lymphoblastic leukaemia
- 2016
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 7:11790
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Tidskriftsartikel (refereegranskat)abstract
- Fusion genes are potent driver mutations in cancer. In this study, we delineate the fusion gene landscape in a consecutive series of 195 paediatric B-cell precursor acute lymphoblastic leukaemia (BCP ALL). Using RNA sequencing, we find in-frame fusion genes in 127 (65%) cases, including 27 novel fusions. We describe a subtype characterized by recurrent IGH-DUX4 or ERG-DUX4 fusions, representing 4% of cases, leading to overexpression of DUX4 and frequently co-occurring with intragenic ERG deletions. Furthermore, we identify a subtype characterized by an ETV6-RUNX1-like gene-expression profile and coexisting ETV6 and IKZF1 alterations. Thus, this study provides a detailed overview of fusion genes in paediatric BCP ALL and adds new pathogenetic insights, which may improve risk stratification and provide therapeutic options for this disease.
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| 3. |
- Pronk, Cornelis J. H., et al.
(författare)
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Elucidation of the phenotypic, functional, and molecular topography of a myeloerythroid progenitor cell hierarchy
- 2007
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Ingår i: Cell Stem Cell. - : Elsevier (Cell Press). - 1934-5909 .- 1875-9777. ; 1:4, s. 428-442
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Tidskriftsartikel (refereegranskat)abstract
- The major myeloid blood cell lineages are generated from hematopoietic stem cells by differentiation through a series of increasingly committed progenitor cells. Precise characterization of intermediate progenitors is important for understanding fundamental differentiation processes and a variety of disease states, including leukemia. Here, we evaluated the functional in vitro and in vivo potentials of a range of prospectively isolated myeloid precursors with differential expression of CD150, Endoglin, and CD41. Our studies revealed a hierarchy of myeloerythroid progenitors with distinct lineage potentials. The global gene expression signatures of these subsets were consistent with their functional capacities, and hierarchical clustering analysis suggested likely lineage relationships. These studies provide valuable tools for understanding myeloid lineage commitment, including isolation of an early erythroid-restricted precursor, and add to existing models of hematopoietic differentiation by suggesting that progenitors of the innate and adaptive immune system can separate late, following the divergence of megakaryocytic/erythroid potential.
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| 4. |
- Eguíluz-Gracia, Ibon, et al.
(författare)
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Long-Term persistence of human donor alveolar macrophages in lung transplant recipients
- 2016
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Ingår i: Thorax. - : BMJ. - 0040-6376 .- 1468-3296. ; 71:11, s. 1006-1011
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Tidskriftsartikel (refereegranskat)abstract
- Background Alveolar macrophages (AMFs) are critical regulators of lung function, and may participate in graft rejection following lung transplantation. Recent studies in experimental animals suggest that most AMFs are self-maintaining cells of embryonic origin, but knowledge about the ontogeny and life span of human AMFs is scarce. Methods To follow the origin and longevity of AMFs in patients with lung transplantation for more than 100â €..weeks, we obtained transbronchial biopsies from 10 gender-mismatched patients with lung transplantation. These were subjected to combined in situ hybridisation for X/Y chromosomes and immunofluorescence staining for macrophage markers. Moreover, development of AMFs in humanised mice reconstituted with CD34+ umbilical cord-derived cells was assessed. Results The number of donor-derived AMFs was unchanged during the 2â €..year post-Transplantation period. A fraction of the AMFs proliferated locally, demonstrating that at least a subset of human AMFs have the capacity to self-renew. Lungs of humanised mice were found to abundantly contain populations of human AMFs expressing markers compatible with a monocyte origin. Moreover, in patients with lung transplantation we found that recipient monocytes seeded the alveoli early after transplantation, and showed subsequent phenotypical changes consistent with differentiation into proliferating mature AMFs. This resulted in a stable mixed chimerism between donor and recipient AMFs throughout the 2-year period. Conclusions The finding that human AMFs are maintained in the lung parenchyma for several years indicates that pulmonary macrophage transplantation can be a feasible therapeutic option for patients with diseases caused by dysfunctional AMFs. Moreover, in a lung transplantation setting, long-Term persistence of donor AMFs may be important for the development of chronic graft rejection.
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| 7. |
- Pronk, Cornelis J.H., et al.
(författare)
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Immunophenotypic identification of early myeloerythroid development
- 2018
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Ingår i: Flow Cytometry Protocols. - New York, NY : Springer New York. - 1064-3745. - 9781493973460 ; 1678, s. 301-319
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Bokkapitel (refereegranskat)abstract
- Myeloerythroid-restricted precursor cells, derived from multipotent hematopoietic stem cells, give rise to mature cells of the granulocyte, monocyte, erythroid, and/or thrombocytic lineages. High-resolution profiling of the developmental stages, from hematopoietic stem cells to mature progeny, is important to be able to study and understand the underlying mechanisms that guide various cell fate decisions. Also, this approach opens for greater insights into pathogenic events such as leukemia, diseases that are most often characterized by halted differentiation at defined immature precursor levels. In this chapter, we provide protocols and discuss approaches concerning the analysis and purification of immature myeloerythroid lineages by multiparameter flow cytometry. A wealth of literature has demonstrated the feasibility of similar approaches also for the human system. However, in this chapter, we focus on the identification of bone marrow cells derived from C57BL/6 mice, in which flow cytometry-based immunophenotypic applications have been most widely developed. This should allow also for its application in genetically modified models on this background. For maximal reproducibility, all protocols described have been established using reagents from commercial vendors to be analyzed on a flow cytometer with factory standard configuration.
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