David Bryder

Publications (57) View all

• Article: SOCS2 is dispensable for BCR/ABL1-induced chronic myeloid leukemia-like disease and for normal hematopoietic stem cell function.

  N Hansen, H Agerstam, M Wahlestedt, N Landberg, M Askmyr, M Ehinger, M Rissler, H Lilljebjörn, P Johnels, J Ishiko, J V Melo, W S Alexander, D Bryder, M Järås, T Fioretos
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  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.
  Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 06/2012; · 8.30 Impact Factor
• Article: An epigenetic component of hematopoietic stem cell aging amenable to reprogramming into a young state.

  Martin Wahlestedt, Gudmundur L Norddahl, Gerd Sten, Amol Ugale, Mary-Ann Micha Frisk, Ragnar Mattsson, Tomas Deierborg, Mikael Sigvardsson, David Bryder
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  ABSTRACT: Key points Hematopoietic stem cell aging associate with stable transcriptional alterations that persist through transplantation.Somatic cell reprogramming of aged hematopoietic stem and progenitor cells reverses functional defects associated with hematopoietic aging.
  Blood 03/2013; · 9.90 Impact Factor
• Article: Reduced repression of cytokine signaling ameliorates age-induced decline in hematopoietic stem cell function.

  Gudmundur L Norddahl, Martin Wahlestedt, Santiago Gisler, Mikael Sigvardsson, David Bryder
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  ABSTRACT: Aging causes profound effects on the hematopoietic stem cell (HSC) pool, including an altered output of mature progeny and enhanced self-propagation of repopulating-defective HSCs. An important outstanding question is whether HSCs can be protected from aging. The signal adaptor protein LNK negatively regulates hematopoiesis at several cellular stages. It has remained unclear how the enhanced sensitivity to cytokine signaling caused by LNK deficiency affects hematopoiesis upon aging. Our findings demonstrate that aged LNK(-/-) HSCs displayed a robust overall reconstitution potential and gave rise to a hematopoietic system with a balanced lineage distribution. Although aged LNK(-/-) HSCs displayed a distinct molecular profile in which reduced proliferation was central, little or no difference in the proliferation of aged LNK(-/-) HSCs was observed after transplantation when compared to aged WT HSCs. This coincided with equal telomere maintenance in WT and LNK(-/-) HSCs. Collectively, our studies suggest that enhanced cytokine signaling can counteract functional age-related HSC decline.
  Aging cell 07/2012; · 7.55 Impact Factor
• Article: Dietary L-leucine improves the anemia in a mouse model for Diamond-Blackfan anemia.

  Pekka Jaako, Shubhranshu Debnath, Karin Olsson, David Bryder, Johan Flygare, Stefan Karlsson
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  ABSTRACT: Diamond-Blackfan anemia (DBA) is a congenital erythroid hypoplasia caused by a functional haploinsufficiency of genes encoding for ribosomal proteins. Recently, a case study reported a patient who became transfusion-independent in response to treatment with the amino acid L-leucine. Therefore, we have validated the therapeutic effect of L-leucine using our recently generated mouse model for RPS19-deficient DBA. Administration of L-leucine significantly improved the anemia in Rps19-deficient mice (19% improvement in hemoglobin concentration; 18% increase in the number of erythrocytes), increased the bone marrow cellularity, and alleviated stress hematopoiesis. Furthermore, the therapeutic response to L-leucine appeared specific for Rps19-deficient hematopoiesis and was associated with down-regulation of p53 activity. Our study supports the rationale for clinical trials of L-leucine as a therapeutic agent for DBA.
  Blood 07/2012; 120(11):2225-8. · 9.90 Impact Factor
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  Available from: David Bryder

  Article: Mice with ribosomal protein S19 deficiency develop bone marrow failure and symptoms like patients with Diamond-Blackfan anemia.

  Pekka Jaako, Johan Flygare, Karin Olsson, Ronan Quere, Mats Ehinger, Adrianna Henson, Steven Ellis, Axel Schambach, Christopher Baum, Johan Richter, Jonas Larsson, David Bryder, Stefan Karlsson
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  ABSTRACT: Diamond-Blackfan anemia (DBA) is a congenital erythroid hypoplasia caused by a functional haploinsufficiency of genes encoding for ribosomal proteins. Among these genes, ribosomal protein S19 (RPS19) is mutated most frequently. Generation of animal models for diseases like DBA is challenging because the phenotype is highly dependent on the level of RPS19 down-regulation. We report the generation of mouse models for RPS19-deficient DBA using transgenic RNA interference that allows an inducible and graded down-regulation of Rps19. Rps19-deficient mice develop a macrocytic anemia together with leukocytopenia and variable platelet count that with time leads to the exhaustion of hematopoietic stem cells and bone marrow failure. Both RPS19 gene transfer and the loss of p53 rescue the DBA phenotype implying the potential of the models for testing novel therapies. This study demonstrates the feasibility of transgenic RNA interference to generate mouse models for human diseases caused by haploinsufficient expression of a gene.
  Blood 12/2011; 118(23):6087-96. · 9.90 Impact Factor