| 1. |
- Askmyr, Maria, et al.
(författare)
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Ciliary neurotrophic factor has intrinsic and extrinsic roles in regulating B cell differentiation and bone structure.
- 2015
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- The gp130 receptor and its binding partners play a central role in cytokine signalling. Ciliary neurotrophic factor (CNTF) is one of the cytokines that signals through the gp130 receptor complex. CNTF has previously been shown to be a negative regulator of trabecular bone remodelling and important for motor neuron development. Since haematopoietic cell maintenance and differentiation is dependent on the bone marrow (BM) microenvironment, where cells of the osteoblastic lineage are important regulators, we hypothesised that CNTF may also have important roles in regulating haematopoiesis. Analysis of haematopoietic parameters in male and female Cntf(-/-) mice at 12 and 24 weeks of age revealed altered B lymphopoiesis. Strikingly, the B lymphocyte phenotype differed based on sex, age and also the BM microenvironment in which the B cells develop. When BM cells from wildtype mice were transplanted into Cntf(-/-) mice, there were minimal effects on B lymphopoiesis or bone parameters. However, when Cntf(-/-) BM cells were transplanted into a wildtype BM microenvironment, there were changes in both haematopoiesis and bone parameters. Our data reveal that haematopoietic cell-derived CNTF has roles in regulating BM B cell lymphopoiesis and both trabecular and cortical bone, the latter in a sex-dependent manner.
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| 2. |
- Askmyr, Maria K, et al.
(författare)
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Towards a better understanding and new therapeutics of osteopetrosis.
- 2008
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Ingår i: British journal of haematology. - : Wiley. - 1365-2141 .- 0007-1048. ; 140:6, s. 597-609
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Forskningsöversikt (refereegranskat)abstract
- Lack of or dysfunction in osteoclasts result in osteopetrosis, a group of rare but often severe, genetic disorders affecting skeletal tissue. Increase in bone mass results in skeletal malformation and bone marrow failure that may be fatal. Many of the underlying defects have lately been characterized in humans and in animal models of the disease. In humans, these defects often involve mutations in genes expressing proteins involved in the acidification of the osteoclast resorption compartment, a process necessary for proper bone degradation. So far, the only cure for children with severe osteopetrosis is allogeneic hematopoietic stem cell (HSC) transplantation but without a matching donor this form of therapy is far from optimal. The characterization of the genetic defects opens up the possibility for gene replacement therapy as an alternative. Accordingly, HSC-targeted gene therapy in a mouse model of infantile malignant osteopetrosis was recently shown to correct many aspects of the disease.
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| 3. |
- Askmyr, Maria, et al.
(författare)
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Low-dose busulphan conditioning and neonatal stem cell transplantation preserves vision and restores hematopoiesis in severe murine osteopetrosis.
- 2009
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Ingår i: Experimental Hematology. - : Elsevier BV. - 1873-2399 .- 0301-472X. ; 37, s. 302-308
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Infantile malignant osteopetrosis is a fatal disease caused by lack of functional osteoclasts. In most of patients, TCIRG1, encoding a subunit of a proton pump essential for bone resorption, is mutated. Osteopetrosis leads to bone marrow failure and blindness due to optic nerve compression. Oc/oc mice have a deletion in Tcirg1 and die around 3 to 4 weeks, but can be rescued by neonatal stem cell transplantation (SCT) after irradiation conditioning. However, as irradiation of neonatal mice results in retinal degeneration, we wanted to investigate whether conditioning with busulphan prior to SCT can lead to preservation of vision and reversal of osteopetrosis in the oc/oc mouse model. MATERIALS AND METHODS: Pregnant dams were conditioned with busulphan and their litters transplanted with 1 x 10(6) normal lineage-depleted bone marrow cells intravenously or intraperitoneally. Mice were followed in terms of survival and engraftment level, as well as with peripheral blood lineage analysis, bone and eye histopathology and a visual-tracking drum test to assess vision. RESULTS: Busulphan at 15 mg/kg was toxic to oc/oc mice. However, six of seven oc/oc mice conditioned with busulphan 7.5 mg/kg survived past the normal lifespan with 10% engraftment, correction of the skeletal phenotype, and normalization of peripheral blood lineages. Busulphan, in contrast to irradiation, did not have adverse effects on the retina as determined by histopathology, and 8 weeks after transplantation control and oc/oc mice retained their vision. CONCLUSION: Low-dose busulphan conditioning and neonatal SCT leads to prolonged survival of oc/oc mice, reverses osteopetrosis and prevents blindness even at low engraftment levels.
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| 4. |
- Johansson, M. K., et al.
(författare)
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Hematopoietic stem cell-targeted neonatal gene therapy reverses lethally progressive osteopetrosis in oc/oc mice
- 2007
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 109:12, s. 5178-85
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Tidskriftsartikel (refereegranskat)abstract
- Infantile malignant osteopetrosis (IMO) is a fatal disease caused by lack of functional osteoclasts, and the only available treatment is hematopoietic stem cell (HSC) transplantation. In the majority of patients, the TCIRG1 gene, coding for a subunit of a proton pump essential for bone resorption, is mutated. Oc/oc mice have a deletion in the homologue gene (tcirg1) and die at 3 to 4 weeks, but can be rescued by neonatal transplantation of HSCs. Here, HSC-targeted gene therapy of osteopetrosis in the oc/oc mouse model was developed. Oc/oc fetal liver cells depleted of Ter119-expressing erythroid cells were transduced with a retroviral vector expressing tcirg1 and GFP, and subsequently transplanted intraperitoneally to irradiated neonatal oc/oc mice. Eight of 15 mice survived past the normal life span of oc/oc mice. In vitro osteoclastogenesis revealed formation of GFP-positive osteoclasts and bone resorption, albeit at a lower level than from wild-type cells. The skeletal phenotype was analyzed by X-ray and histopathology and showed partial correction at 8 weeks and almost normalization after 18 weeks. In summary, osteopetrosis in oc/oc mice can be reversed by neonatal transplantation of gene-modified HSCs leading to long-term survival. This represents a significant step toward the development of gene therapy for osteopetrosis.
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| 5. |
- 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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