| 21. |
- Davidsson, Josef, et al.
(författare)
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SAMD9 and SAMD9L in inherited predisposition to ataxia, pancytopenia, and myeloid malignancies
- 2018
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 32:5, s. 1106-1115
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Tidskriftsartikel (refereegranskat)abstract
- Germline mutations in the SAMD9 and SAMD9L genes, located in tandem on chromosome 7, are associated with a clinical spectrum of disorders including the MIRAGE syndrome, ataxia–pancytopenia syndrome and myelodysplasia and leukemia syndrome with monosomy 7 syndrome. Germline gain-of-function mutations increase SAMD9 or SAMD9L’s normal antiproliferative effect. This causes pancytopenia and generally restricted growth and/or specific organ hypoplasia in non-hematopoietic tissues. In blood cells, additional somatic aberrations that reverse the germline mutation’s effect, and give rise to the clonal expansion of cells with reduced or no antiproliferative effect of SAMD9 or SAMD9L include complete or partial chromosome 7 loss or loss-of-function mutations in SAMD9 or SAMD9L. Furthermore, the complete or partial loss of chromosome 7q may cause myelodysplastic syndrome in these patients. SAMD9 mutations appear to associate with a more severe disease phenotype, including intrauterine growth restriction, developmental delay and hypoplasia of adrenal glands, testes, ovaries or thymus, and most reported patients died in infancy or early childhood due to infections, anemia and/or hemorrhages. SAMD9L mutations have been reported in a few families with balance problems and nystagmus due to cerebellar atrophy, and may lead to similar hematological disease as seen in SAMD9 mutation carriers, from early childhood to adult years. We review the clinical features of these syndromes, discuss the underlying biology, and interpret the genetic findings in some of the affected family members. We provide expert-based recommendations regarding diagnosis, follow-up, and treatment of mutation carriers.
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| 22. |
- Dudenhöffer-Pfeifer, Monika, et al.
(författare)
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Immunoediting is not a primary transformation event in a murine model of MLL-ENL AML
- 2018
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Ingår i: Life Science Alliance. - : Life Science Alliance, LLC. - 2575-1077. ; 1:4
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Tidskriftsartikel (refereegranskat)abstract
- Although it is firmly established that endogenous immunity can prevent cancer outgrowth, with a range of immunomodulatory strategies reaching clinical use, most studies on the topic have been restricted to solid cancers. This applies in particular to cancer initiation, where model constraints have precluded investigations of immunosurveillance and immunoediting during the multistep progression into acute myeloid leukemia (AML). Here, we used a mouse model where the chimeric transcription factor MLL-ENL can be conditionally activated in vivo as a leukemic “first-hit,” which is followed by spontaneous transformation into AML. We observed similar disease kinetics regardless of whether AML developed in WT or immunocompromised hosts, despite more permissive preleukemic environments in the latter. When assessing transformed AML cells from either primary immunocompetent or immunocompromised hosts, AML cells from all sources could be targets of endogenous immunity. Our data argue against immunoediting in response to selective pressure from endogenous immunity as a universal primary transformation event in AML.
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| 23. |
- Dybedal, Ingunn, et al.
(författare)
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Tumor necrosis factor (TNF)-mediated activation of the p55 TNF receptor negatively regulates maintenance of cycling reconstituting human hematopoietic stem cells
- 2001
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Ingår i: Blood. - 1528-0020. ; 98:6, s. 1782-1791
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Tidskriftsartikel (refereegranskat)abstract
- Hematopoietic stem cell (HSC) fate decisions between self-renewal and commitment toward differentiation are tightly regulated in vivo. Recent developments in HSC culture and improvements of human HSC assays have facilitated studies of these processes in vitro. Through such studies stimulatory cytokines critically involved in HSC maintenance in vivo have been demonstrated to also promote HSC self-renewing divisions in vitro. Evidence for negative regulators of HSC self-renewal is, however, lacking. Tumor necrosis factor (TNF), if overexpressed, has been implicated to mediate bone marrow suppression. However, whether and how TNF might affect the function of HSC with a combined myeloid and lymphoid reconstitution potential has not been investigated. In the present studies in vitro conditions recently demonstrated to promote HSC self-renewing divisions in vitro were used to study the effect of TNF on human HSCs capable of reconstituting myelopoiesis and lymphopoiesis in nonobese diabetic-severe combined immunodeficient (NOD-SCID) mice. Although all cord blood and adult bone marrow CD34(+)CD38(-) cells were capable of undergoing cell divisions in the presence of TNF, cycling HSCs exposed to TNF in vitro and in vivo were severely compromised in their ability to reconstitute NOD-SCID mice and long-term cultures. The negative effect of TNF was not dependent on the Fas pathway, and a similar effect could be observed using a mutant TNF exclusively targeting the p55 TNF receptor. TNF did not appear to enhance apoptosis or affect cell-cycle distribution of cultured progenitors, but rather promoted myeloid differentiation. Thus, TNF might regulate HSC fate by promoting their differentiation rather than self-renewal.
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| 24. |
- Eldeeb, Mohamed, et al.
(författare)
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A fetal tumor suppressor axis abrogates MLL-fusion-driven acute myeloid leukemia
- 2023
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 42:2
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Tidskriftsartikel (refereegranskat)abstract
- MLL-rearrangements (MLL-r) are recurrent genetic events in acute myeloid leukemia (AML) and frequently associate with poor prognosis. In infants, MLL-r can be sufficient to drive transformation. However, despite the prenatal origin of MLL-r in these patients, congenital leukemia is very rare with transformation usually occurring postnatally. The influence of prenatal signals on leukemogenesis, such as those mediated by the fetal-specific protein LIN28B, remains controversial. Here, using a dual-transgenic mouse model that co-expresses MLL-ENL and LIN28B, we investigate the impact of LIN28B on AML. LIN28B impedes the progression of MLL-r AML through compromised leukemia-initiating cell activity and suppression of MYB signaling. Mechanistically, LIN28B directly binds to MYBBP1A mRNA, resulting in elevated protein levels of this MYB co-repressor. Functionally, overexpression of MYBBP1A phenocopies the tumor-suppressor effects of LIN28B, while its perturbation omits it. Thereby, we propose that developmentally restricted expression of LIN28B provides a layer of protection against MYB-dependent AML.
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| 25. |
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| 26. |
- Elias, Harold K., et al.
(författare)
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Molecular mechanisms underlying lineage bias in aging hematopoiesis
- 2017
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Ingår i: Seminars in Hematology. - : Elsevier BV. - 0037-1963. ; 54:1, s. 4-11
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Forskningsöversikt (refereegranskat)abstract
- Although hematopoietic stem cells (HSCs) have traditionally been thought to possess the ability to give rise to all the mature cell types in the hematopoietic system, this conception of hematopoiesis was based on evaluation of hematopoietic output from large numbers of HSCs using transplantation models. More recent studies evaluating HSCs at the clonal or near-clonal level, both in transplantation studies and during in situ hematopoiesis, have established that individual HSCs can exhibit lineage bias, giving rise to myeloid-biased, lymphoid-biased, or more balanced differentiation, with the proportion of myeloid-biased HSCs increasing with age. This age-associated shift in lineage potential is associated with decreased cellular immunity and increased incidence of diseases with prominent inflammatory components including atherosclerosis, autoimmunity, neurodegenerative disease, and carcinogenesis. Understanding the molecular mechanisms that regulate this shift in linage bias therefore represents an important area of investigation in numerous human diseases. In this review, we summarize our current understanding of the cell-intrinsic (autonomous) and cell-extrinsic factors that regulate HSC lineage fate bias during aging. In addition, we have attempted to bring attention to important caveats and unanswered questions related to the issue of HSC lineage bias to encourage explorations of these important lines of inquiry. Ultimately, we expect a comprehensive understanding of HSC lineage bias during aging to have important implications for human health, since strategies to alter lineage bias in old HSCs not only has the potential to restore immune function in the elderly, but also to reduce the incidence of inflammation-associated diseases, many for which there is a current unmet need for novel and more effective treatments.
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| 27. |
- Engelhard, Sophia, et al.
(författare)
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Endomucin marks quiescent long-term multi-lineage repopulating hematopoietic stem cells and is essential for their transendothelial migration
- 2024
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Ingår i: Cell Reports. - 2211-1247. ; 43:7
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Tidskriftsartikel (refereegranskat)abstract
- Endomucin (EMCN) currently represents the only hematopoietic stem cell (HSC) marker expressed by both murine and human HSCs. Here, we report that EMCN+ long-term repopulating HSCs (LT-HSCs; CD150+CD48−LSK) have a higher long-term multi-lineage repopulating capacity compared to EMCN− LT-HSCs. Cell cycle analyses and transcriptional profiling demonstrated that EMCN+ LT-HSCs were more quiescent compared to EMCN− LT-HSCs. Emcn−/− and Emcn+/+ mice displayed comparable steady-state hematopoiesis, as well as frequencies, transcriptional programs, and long-term multi-lineage repopulating capacity of their LT-HSCs. Complementary functional analyses further revealed increased cell cycle entry upon treatment with 5-fluorouracil and reduced granulocyte colony-stimulating factor (GCSF) mobilization of Emcn−/− LT-HSCs, demonstrating that EMCN expression by LT-HSCs associates with quiescence in response to hematopoietic stress and is indispensable for effective LT-HSC mobilization. Transplantation of wild-type bone marrow cells into Emcn−/− or Emcn+/+ recipients demonstrated that EMCN is essential for endothelial cell-dependent maintenance/self-renewal of the LT-HSC pool and sustained blood cell production post-transplant.
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| 28. |
- Hansen, Nils, et al.
(författare)
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SOCS2 is dispensable for BCR/ABL1-induced chronic myeloid leukemia-like disease and for normal hematopoietic stem cell function.
- 2013
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 27, s. 130-135
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Tidskriftsartikel (refereegranskat)abstract
- Suppressor of cytokine signaling 2 (SOCS2) is known as a feedback inhibitor of cytokine signaling and is highly expressed in primary bone marrow (BM) cells from patients with chronic myeloid leukemia (CML). However, it has not been established whether SOCS2 is involved in CML, caused by the BCR/ABL1 fusion gene, or important for normal hematopoietic stem cell (HSC) function. In this study, we demonstrate that although Socs2 was found to be preferentially expressed in long-term HSCs, Socs2-deficient HSCs were indistinguishable from wild-type HSCs when challenged in competitive BM transplantation experiments. Furthermore, by using a retroviral BCR/ABL1-induced mouse model of CML, we demonstrate that SOCS2 is dispensable for the induction and propagation of the disease, suggesting that the SOCS2-mediated feedback regulation of the JAK/STAT pathway is deficient in BCR/ABL1-induced CML.Leukemia advance online publication, 24 July 2012; doi:10.1038/leu.2012.169.
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| 29. |
- Hidalgo, Isabel, et al.
(författare)
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Bmi1 induction protects hematopoietic stem cells against pronounced long-term hematopoietic stress
- 2022
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Ingår i: Experimental Hematology. - : Elsevier BV. - 1873-2399 .- 0301-472X. ; 109, s. 35-44
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Tidskriftsartikel (refereegranskat)abstract
- The Polycomb complex protein Bmi1 is regarded as a master regulator of hematopoietic stem cells (HSCs). In the blood system, HSCs express Bmi1 most abundantly and Bmi1 expression vanes as cells differentiate. Furthermore, Bmi1 has been found overexpressed in several hematologic cancers. Most studies exploring the normal role of Bmi1 in HSC biology have utilized loss-of-function models, which have established Bmi1 as an important regulator for HSC maintenance. Additionally, gain-of-function studies using retroviral and lentiviral approaches have observed increased self-renewal of Bmi-1 transduced HSCs. However, the clinical and biological relevance of such studies are typically hampered by uncontrolled transgenic integration and supraphysiological expression levels. Here, we developed a novel Tetracycline-inducible gain-of-function Bmi1 (iBmi1) transgenic mouse model. We find that Bmi1 induction had minor, if any, effects on steady-state hematopoiesis or following 5-fluorouracil-induced cytostatic stress. On the contrary, secondary transplantation of iBmi1 HSCs into wild type recipients resulted in remarkable increases of HSC numbers and chimerism levels. These data, in concert with previous loss-of-function studies, suggest that while endogenous Bmi1 levels are required and sufficient for normal HSC maintenance, the stabilization of these levels over time protects HSC from transplantation-associated stress.
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| 30. |
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