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1.
  • Adolfsson, Jörgen, et al. (författare)
  • Identification of Flt3(+) lympho-myeloid stem cells lacking erythro-megakaryocytic potential: A revised road map for adult blood lineage commitment
  • 2005
  • Ingår i: Cell. - : Cell Press. - 1097-4172 .- 0092-8674. ; 121:2, s. 295-306
  • Tidskriftsartikel (refereegranskat)abstract
    • All blood cell lineages derive from a common hematopoietic stem cell (HSC). The current model implicates that the first lineage commitment step of adult pluripotent HSCs results in a strict separation into common lymphoid and common myeloid precursors. We present evidence for a population of cells which, although sustaining a high proliferative and combined lympho-myeloid differentiation potential, have lost the ability to adopt erythroid and megakaryocyte lineage fates. Cells in the Lin-Sca-1+c-kit+ HSC compartment coexpressing high levels of the tyrosine kinase receptor Flt3 sustain granulocyte, monocyte, and B and T cell potentials but in contrast to Lin-Sca-1(+)ckit(+)Flt3(-) HSCs fail to produce significant erythroid and megakaryocytic progeny. This distinct lineage restriction site is accompanied by downregulation of genes for regulators of erythroid and megakaryocyte development. In agreement with representing a lymphoid primed progenitor, Lin(-)Sca-l(+)c-kit(+)CD34(+)Flt3(+) cells display upregulated IL-7 receptor gene expression. Based on these observations, we propose a revised road map for adult blood lineage development.
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2.
  • Garrison, Brian S, et al. (författare)
  • ZFP521 regulates murine hematopoietic stem cell function and facilitates MLL-AF9 leukemogenesis in mouse and human cells
  • 2017
  • Ingår i: Blood. - : American Society of Hematology. - 0006-4971. ; 130:5, s. 619-624
  • Tidskriftsartikel (refereegranskat)abstract
    • The concept that tumor-initiating cells can co-opt the self-renewal program of endogenous stem cells as a means of enforcing their unlimited proliferative potential is widely accepted, yet identification of specific factors that regulate self-renewal of normal and cancer stem cells remains limited. Using a comparative transcriptomic approach, we identify ZNF521/Zfp521 as a conserved hematopoietic stem cell (HSC)–enriched transcription factor in human and murine hematopoiesis whose function in HSC biology remains elusive. Competitive serial transplantation assays using Zfp521-deficient mice revealed that ZFP521 regulates HSC self-renewal and differentiation. In contrast, ectopic expression of ZFP521 in HSCs led to a robust maintenance of progenitor activity in vitro. Transcriptional analysis of human acute myeloid leukemia (AML) patient samples revealed that ZNF521 is highly and specifically upregulated in AMLs with MLL translocations. Using an MLL-AF9 murine leukemia model and serial transplantation studies, we show that ZFP521 is not required for leukemogenesis, although its absence leads to a significant delay in leukemia onset. Furthermore, knockdown of ZNF521 reduced proliferation in human leukemia cell lines possessing MLL-AF9 translocations. Taken together, these results identify ZNF521/ZFP521 as a critical regulator of HSC function, which facilitates MLL-AF9–mediated leukemic disease in mice.
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3.
  • Jaako, Pekka, et al. (författare)
  • Disruption of the 5S RNP-Mdm2 interaction significantly improves the erythroid defect in a mouse model for Diamond-Blackfan anemia.
  • 2015
  • Ingår i: Leukemia. - : Nature Publishing Group. - 1476-5551. ; 29:11, s. 2221-2229
  • Tidskriftsartikel (refereegranskat)abstract
    • Diamond-Blackfan anemia (DBA) is a congenital erythroid hypoplasia caused by haploinsufficiency of genes encoding ribosomal proteins (RPs). Perturbed ribosome biogenesis in DBA has been shown to induce a p53-mediated ribosomal stress response. However, the mechanisms of p53 activation and its relevance for the erythroid defect remain elusive. Previous studies have indicated that activation of p53 is caused by the inhibition of Mdm2, the main negative regulator of p53, by the 5S ribonucleoprotein particle (RNP). Meanwhile, it is not clear whether this mechanism solely mediates the p53-dependent component found in DBA. To approach this question, we crossed our mouse model for RPS19-deficient DBA with Mdm2(C305F) knock-in mice that have a disrupted 5S RNP-Mdm2 interaction. Upon induction of the Rps19 deficiency, Mdm2(C305F) reversed the p53 response and improved expansion of hematopoietic progenitors in vitro, and ameliorated the anemia in vivo. Unexpectedly, disruption of the 5S RNP-Mdm2 interaction also led to selective defect in erythropoiesis. Our findings highlight the sensitivity of erythroid progenitor cells to aberrations in p53 homeostasis mediated by the 5S RNP-Mdm2 interaction. Finally, we provide evidence indicating that physiological activation of the 5S RNP-Mdm2-p53 pathway may contribute to functional decline of the hematopoietic system in a cell-autonomous manner over time.Leukemia accepted article preview online, 19 May 2015. doi:10.1038/leu.2015.128.
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4.
  • Månsson, Robert, et al. (författare)
  • Single cell analysis of the common lymphoid progenitor compartment reveals functional and molecular heterogeneity.
  • 2010
  • Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 115:13, s. 2601-2609
  • Tidskriftsartikel (refereegranskat)abstract
    • In order to investigate molecular events involved in the regulation of lymphoid lineage commitment, we crossed lambda5 reporter transgenic mice to Rag1-GFP knock in mice. This allowed us to sub-fractionate common lymphoid progenitors (CLPs) and pre-pro-B (Fraction A) cells into lambda5(-)Rag1(low), lambda5(-)Rag1(high) and lambda5(+)Rag1(high) cells. Clonal in vitro differentiation analysis demonstrated that Rag1(low) cells gave rise to B/T and NK cells. Rag1(high) cells displayed reduced NK-cell potential with preserved capacity to generate B- and T-lineage cells, while the lambda5(+) cells were B-lineage restricted. Ebf1 and Pax5 expression was largely confined to the Rag1(high) populations. These cells also expressed a higher level of the surface protein LY6D, providing an additional tool for the analysis of early lymphoid development. These data suggest that the classical CLP compartment comprises a mixture of cells with relatively restricted lineage potentials, thus opening new possibilities to investigate early hematopoiesis.
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5.
  • Nilsson, Lars, et al. (författare)
  • Involvement and functional impairment of the CD34(+)CD38(-)Thy-1(+) hematopoietic stem cell pool in myelodysplastic syndromes with trisomy 8.
  • 2002
  • Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 100:1, s. 259-267
  • Tidskriftsartikel (refereegranskat)abstract
    • Clonality studies of mature cells suggest that the primary transformation event in myelodysplastic syndrome (MDS) most frequently occurs in a myeloid-restricted progenitor, a hypothesis supported by recent studies of purified CD34(+)Thy1(+) hematopoietic stem cells (HSCs) in cases with trisomy 8 (+8). In contrast, we recently demonstrated that a lymphomyeloid HSC is the target for transformation in MDS cases with del(5q), potentially reflecting heterogeneity within MDS. However, since +8 is known to frequently be a late event in the MDS transformation process, it remained a possibility that CD34(+)CD38(-)Thy1(+) HSC disomic for chromosome 8 might be part of the MDS clone. In the present studies, although a variable fraction of CD34(+)CD38(-)Thy1(+) cells were disomic for chromosome 8, they did not possess normal HSC activity in long-term cultures and nonobese diabetic-severe combined immunodeficiency (NOD-SCID) mice. Mixing experiments with normal CD34(+)CD38(-) cells suggested that this HSC deficiency was intrinsic and not mediated by indirect mechanisms. Furthermore, investigation of 4 MDS cases with combined del(5q) and +8 demonstrated that the +8 aberration was always secondary to del(5q). Whereas del(5q) invariably occurs in CD34(+)CD38(-)Thy-1(+) HSCs, the secondary +8 event might frequently arise in progeny of MDS HSCs. Thus, CD34(+)CD38(-)Thy1(+) HSCs are invariably part of the MDS clone also in +8 patients, and little HSC activity can be recovered from the CD34(+) CD38(-)Thy1(+) HSC. Finally, in advanced cases of MDS, the MDS reconstituting activity is exclusively derived from the minor CD34(+)CD38(-) HSC population, demonstrating that MDS stem cells have a similar phenotype as normal HSCs, potentially complicating the development of autologous transplantation for MDS.
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6.
  • Sitnicka Quinn, Ewa, et al. (författare)
  • Complementary Signaling through flt3 and Interleukin-7 Receptor {alpha} Is Indispensable for Fetal and Adult B Cell Genesis.
  • 2003
  • Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 198:10, s. 1495-1506
  • Tidskriftsartikel (refereegranskat)abstract
    • Extensive studies of mice deficient in one or several cytokine receptors have failed to support an indispensable role of cytokines in development of multiple blood cell lineages. Whereas B1 B cells and Igs are sustained at normal levels throughout life of mice deficient in IL-7, IL-7R{alpha}, common cytokine receptor gamma chain, or flt3 ligand (FL), we report here that adult mice double deficient in IL-7R{alpha} and FL completely lack visible LNs, conventional IgM+ B cells, IgA+ plasma cells, and B1 cells, and consequently produce no Igs. All stages of committed B cell progenitors are undetectable in FL-/- x IL-7R{alpha}-/- BM that also lacks expression of the B cell commitment factor Pax5 and its direct target genes. Furthermore, in contrast to IL-7R{alpha}-/- mice, FL-/- x IL-7R{alpha}-/- mice also lack mature B cells and detectable committed B cell progenitors during fetal development. Thus, signaling through the cytokine tyrosine kinase receptor flt3 and IL-7R{alpha} are indispensable for fetal and adult B cell development.
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7.
  • Tesi, Bianca, et al. (författare)
  • Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS and neurological symptoms
  • 2017
  • Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 129:16, s. 2266-2279
  • Tidskriftsartikel (refereegranskat)abstract
    • Several monogenic causes of familial myelodysplastic syndrome (MDS) have recently been identified. We studied two families with cytopenia, predisposition to MDS with chromosome 7 aberrations, immunodeficiency, and progressive cerebellar dysfunction. Genetic studies uncovered heterozygous missense mutations in SAMD9L, a tumor suppressor gene located on chromosome arm 7q. Consistent with a gain-of-function effect, ectopic expression of the two identified SAMD9L mutants decreased cell proliferation relative to wild-type protein. Of the ten individuals identified heterozygous for either SAMD9L mutation, three developed MDS upon loss of the mutated SAMD9L allele following intracellular infections associated with myeloid, B and NK cell deficiency. Five other individuals, three with spontaneously resolved cytopenic episodes in infancy, harbored hematopoietic revertant mosaicism by uniparental disomy of 7q with loss of the mutated allele or additional in cis SAMD9L truncating mutations. Examination of one individual indicated that somatic reversions were postnatally selected. Somatic mutations were tracked to CD34(+) hematopoietic progenitor cell populations, being further enriched in B and NK cells. Stimulation of these cell types with interferon (IFN)-α or -γ induced SAMD9L expression. Clinically, revertant mosaicism was associated with milder disease, yet neurological manifestations persisted in three individuals. Two carriers also harbored a rare, in trans germline SAMD9L missense loss-of-function variant, potentially counteracting the SAMD9L mutation. Our results demonstrate that gain-of-function mutations in the tumor suppressor SAMD9L cause cytopenia, immunodeficiency, variable neurological presentation, and predisposition to MDS with -7/del(7q), where hematopoietic revertant mosaicism commonly ameliorated clinical manifestations. The findings suggest a role for SAMD9L in regulating IFN-driven, demand-adapted hematopoiesis.
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8.
  • Welinder, Eva, et al. (författare)
  • The transcription factors E2A and HEB act in concert to induce the expression of FOXO1 in the common lymphoid progenitor
  • 2011
  • Ingår i: Proceedings of the National Academy of Sciences. - : National Acad Sciences. - 1091-6490 .- 0027-8424. ; 108:42, s. 17402-17407
  • Tidskriftsartikel (refereegranskat)abstract
    • Recent studies have identified a number of transcriptional regulators, including E proteins, EBF1, FOXO1, and PAX5, that act together to orchestrate the B-cell fate. However, it still remains unclear as to how they are linked at the earliest stages of B-cell development. Here, we show that lymphocyte development in HEB-ablated mice exhibits a partial developmental arrest, whereas B-cell development in E2A(+/-)HEB(-/)-mice is completely blocked at the LY6D(-) common lymphoid progenitor stage. We show that the transcription signatures of E2A-and HEB-ablated common lymphoid progenitors significantly overlap. Notably, we found that Foxo1 expression was substantially reduced in the LY6D-HEB-and E2A-deficient cells. Finally, we show that E2A binds to enhancer elements across the FOXO1 locus to activate Foxo1 expression, linking E2A and FOXO1 directly in a common pathway. In summary, the data indicate that the earliest event in B-cell specification involves the induction of FOXO1 expression and requires the combined activities of E2A and HEB.
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9.
  • Zetterblad, Jenny, et al. (författare)
  • Genomics based analysis of interactions between developing B-lymphocytes and stromal cells reveal complex interactions and two-way communication
  • 2010
  • Ingår i: BMC Genomics. - : BioMed Central (BMC). - 1471-2164. ; 11
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The use of functional genomics has largely increased our understanding of cell biology and promises to help the development of systems biology needed to understand the complex order of events that regulates cellular differentiation in vivo. One model system clearly dependent on the integration of extra and intra cellular signals is the development of B-lymphocytes from hematopoietic stem cells in the bone marrow. This developmental pathway involves several defined differentiation stages associated with specific expression of genes including surface markers that can be used for the prospective isolation of the progenitor cells directly from the bone marrow to allow for ex vivo gene expression analysis. The developmental process can be simulated in vitro making it possible to dissect information about cell/cell communication as well as to address the relevance of communication pathways in a rather direct manner. Thus we believe that B-lymphocyte development represents a useful model system to take the first steps towards systems biology investigations in the bone marrow. Results: In order to identify extra cellular signals that promote B lymphocyte development we created a database with approximately 400 receptor ligand pairs and software matching gene expression data from two cell populations to obtain information about possible communication pathways. Using this database and gene expression data from NIH3T3 cells (unable to support B cell development), OP-9 cells (strongly supportive of B cell development), pro-B and pre-B cells as well as mature peripheral B-lineage cells, we were able to identify a set of potential stage and stromal cell restricted communication pathways. Functional analysis of some of these potential ways of communication allowed us to identify BMP-4 as a potent stimulator of B-cell development in vitro. Further, the analysis suggested that there existed possibilities for progenitor B cells to send signals to the stroma. The functional consequences of this were investigated by co-culture experiments revealing that the co-incubation of stromal cells with B cell progenitors altered both the morphology and the gene expression pattern in the stromal cells. Conclusions: We believe that this gene expression data analysis method allows for the identification of functionally relevant interactions and therefore could be applied to other data sets to unravel novel communication pathways.
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10.
  • Adolfsson, Jörgen, et al. (författare)
  • Upregulation of Flt3 expression within the bone marrow Lin(-)Sca1(+)c-kit(+) stem cell compartment is accompanied by loss of self-renewal capacity
  • 2001
  • Ingår i: Immunity. - : Cell Press. - 1074-7613. ; 15:4, s. 659-669
  • Tidskriftsartikel (refereegranskat)abstract
    • Flt3 has emerged as a potential regulator of hematopoietic stem cells (HSC). Sixty percent of cells in the mouse marrow Lin(-)Sca1(+)c-kit(+) HSC pool expressed flt3. Although single cell cloning showed comparable high proliferative, myeloid, B, and T cell potentials of Lin(-)Sca1(+)c-kit(+)flt3(+) and Lin(-)Sca1(+)c-kit(+)flt3(-) cells, only Lin(-)Sca1(+)c-kit(+)flt3(-) cells supported sustained multilineage reconstitution. In striking contrast, Lin(-)Sca1(+)c-kit(+)flt3(+) cells rapidly and efficiently reconstituted B and T lymphopoiesis, whereas myeloid reconstitution was exclusively short term. Unlike c-kit, activation of flt3 failed to support survival of HSC, whereas only flt3 mediated survival of Lin(-)Sca1(+)c-kit(+)flt3(+) reconstituting cells. Phenotypic and functional analysis support that Lin(-)Sca1(+)c-kit(+)flt3(+) cells are progenitors for the common lymphoid progenitor. Thus, upregulation of flt3 expression on Lin(-)Sca1(+)c-kit(+) HSC cells is accompanied by loss of self-renewal capacity but sustained lymphoid-restricted reconstitution potential.
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