| 1. |
- Singbrant, Sofie, et al.
(författare)
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The SKI proto-oncogene enhances the in vivo repopulation of hematopoietic stem cells and causes myeloproliferative disease
- 2014
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 1592-8721 .- 0390-6078. ; 99:4, s. 647-655
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Tidskriftsartikel (refereegranskat)abstract
- The proto-oncogene SKI is highly expressed in human myeloid leukemia and also in murine hematopoietic stem cells. However, its operative relevance in these cells remains elusive. We have over-expressed SKI to define its intrinsic role in hematopoiesis and myeloid neoplasms, which resulted in a robust competitive advantage upon transplantation, a complete dominance of the stem and progenitor compartments, and a marked enhancement of myeloid differentiation at the expense of other lineages. Accordingly, enforced expression of SKI induced a gene signature associated with hematopoietic stem cells and myeloid differentiation, as well as hepatocyte growth factor signaling. Here we demonstrate that, in contrast to what has generally been assumed, the significant impact of SKI on hematopoiesis is independent of its ability to inhibit TGF-beta signaling. Instead, myeloid progenitors expressing SKI are partially dependent on functional hepatocyte growth factor signaling. Collectively our results demonstrate that SKI is an important regulator of hematopoietic stem cell activity and its overexpression leads to myeloproliferative disease.
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| 2. |
- 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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| 3. |
- Capellera-Garcia, Sandra, et al.
(författare)
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Defining the Minimal Factors Required for Erythropoiesis through Direct Lineage Conversion
- 2016
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 15:11, s. 2550-2562
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Tidskriftsartikel (refereegranskat)abstract
- Erythroid cell commitment and differentiation proceed through activation of a lineage-restricted transcriptional network orchestrated by a group of well characterized genes. However, the minimal set of factors necessary for instructing red blood cell (RBC) development remains undefined. We employed a screen for transcription factors allowing direct lineage reprograming from fibroblasts to induced erythroid progenitors/precursors (iEPs). We show that Gata1, Tal1, Lmo2, and c-Myc (GTLM) can rapidly convert murine and human fibroblasts directly to iEPs. The transcriptional signature of murine iEPs resembled mainly that of primitive erythroid progenitors in the yolk sac, whereas addition of Klf1 or Myb to the GTLM cocktail resulted in iEPs with a more adult-type globin expression pattern. Our results demonstrate that direct lineage conversion is a suitable platform for defining and studying the core factors inducing the different waves of erythroid development.
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| 4. |
- Chalk, Alistair M, et al.
(författare)
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Gene expression profiling to define the cell intrinsic role of the SKI proto-oncogene in hematopoiesis and myeloid neoplasms.
- 2014
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Ingår i: Genomics Data. - : Elsevier BV. - 2213-5960. ; 2, s. 189-191
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Tidskriftsartikel (refereegranskat)abstract
- The proto-oncogene SKI is highly expressed in human myeloid leukemia and also in murine hematopoietic stem cells. However, its operative relevance in these cells remains elusive. We have over-expressed SKI to define its intrinsic role in hematopoiesis and myeloid neoplasms, which resulted in a robust competitive advantage upon transplantation, a complete dominance of the stem and progenitor compartments, and a marked enhancement of myeloid differentiation at the expense of other lineages. Accordingly, enforced expression of SKI induced gene signatures associated with hematopoietic stem cells and myeloid differentiation. Here we provide detailed experimental methods and analysis for the gene expression profiling described in our recently published study of Singbrant et al. (2014) in Haematologica. Our data sets (available at http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE39457) provide a resource for exploring the underlying molecular mechanisms of the involvement of the proto-oncogene SKI in hematopoietic stem cell function and development of myeloid neoplasms.
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| 5. |
- Sen, Taha, et al.
(författare)
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Enhancing mitochondrial function in vivo rescues MDS-like anemia induced by pRb deficiency
- 2020
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Ingår i: Experimental Hematology. - : Elsevier BV. - 0301-472X. ; 88, s. 28-41
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Tidskriftsartikel (refereegranskat)abstract
- Erythropoiesis is intimately coupled to cell division, and deletion of the cell cycle regulator retinoblastoma protein (pRb) causes anemia in mice. Erythroid-specific deletion of pRb has been found to result in inefficient erythropoiesis because of deregulated coordination of cell cycle exit and mitochondrial biogenesis. However, the pathophysiology remains to be fully described, and further characterization of the link between cell cycle regulation and mitochondrial function is needed. To this end we further assessed conditional erythroid-specific deletion of pRb. This resulted in macrocytic anemia, despite elevated levels of erythropoietin (Epo), and an accumulation of erythroid progenitors in the bone marrow, a phenotype strongly resembling refractory anemia associated with myelodysplastic syndromes (MDS). Using high-fractionation fluorescence-activated cell sorting analysis for improved phenotypic characterization, we illustrate that erythroid differentiation was disrupted at the orthochromatic stage. Transcriptional profiling of sequential purified populations revealed failure to upregulate genes critical for mitochondrial function such as Pgc1β, Alas2, and Abcb7 specifically at the block, together with disturbed heme production and iron transport. Notably, deregulated ABCB7 causes ring sideroblastic anemia in MDS patients, and the mitochondrial co-activator PGC1β is heterozygously lost in del5q MDS. Importantly, the anemia could be rescued through enhanced PPAR signaling in vivo via either overexpression of Pgc1β or bezafibrate administration. In conclusion, lack of pRb results in MDS-like anemia with disrupted differentiation and impaired mitochondrial function at the orthochromatic erythroblast stage. Our findings reveal for the first time a role for pRb in heme and iron regulation, and indicate that pRb-induced anemia can be rescued in vivo through therapeutic enhancement of PPAR signaling.
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