Showing papers by "Stefan Karlsson published in 2011"
TL;DR: It is proposed that glial cells are components of a BM niche and maintain HSC hibernation by regulating activation of latent TGF-β, which is produced as a latent form by a variety of cells.
692 citations
TL;DR: The data suggest that Cripto/GRP78 signaling is an important pathway that regulates HSC quiescence and maintains HSCs in hypoxia as an intermediary of HIF-1α.
159 citations
TL;DR: Both RPS19 gene transfer and the loss of p53 rescue the DBA phenotype implying the potential of the models for testing novel therapies, and the feasibility of transgenic RNA interference to generate mouse models for human diseases caused by haploinsufficient expression of a gene.
136 citations
TL;DR: The Smad-signaling pathway is brought into focus, chronicling key concepts and recent advances with respect to TGF-β-superfamily signaling in normal and leukemic hematopoiesis.
Abstract: Hematopoietic stem cells (HSCs) reside in the bone marrow (BM) of adult individuals and function to produce and regenerate the entire blood and immune system over the course of an individual's lifetime. Historically, HSCs are among the most thoroughly characterized tissue-specific stem cells. Despite this, the regulation of fate options, such as self-renewal and differentiation, has remained elusive, partly because of the expansive plethora of factors and signaling cues that govern HSC behavior in vivo. In the BM, HSCs are housed in specialized niches that dovetail the behavior of HSCs with the need of the organism. The Smad-signaling pathway, which operates downstream of the transforming growth factor-β (TGF-β) superfamily of ligands, regulates a diverse set of biological processes, including proliferation, differentiation and apoptosis, in many different organ systems. Much of the function of Smad signaling in hematopoiesis has remained nebulous due to early embryonic lethality of most knockout mouse models. However, recently new data have been uncovered, suggesting that the Smad-signaling circuitry is intimately linked to HSC regulation. In this review, we bring the Smad-signaling pathway into focus, chronicling key concepts and recent advances with respect to TGF-β-superfamily signaling in normal and leukemic hematopoiesis.
112 citations
TL;DR: Interestingly, high levels of the adhesion molecule CD44 on leukemic cells are essential to generate leukemia after removal of the primary event, which suggests that extrinsic niche-dependent factors are also involved in the host-dependent outgrowth of leukemias after withdrawal of HOXA10 overexpression event that initiates the leukemia.
Abstract: Multiple genetic hits are detected in patients with acute myeloid leukemia (AML). To investigate this further, we developed a tetracycline-inducible mouse model of AML, in which the initial transforming event, overexpression of HOXA10, can be eliminated. Continuous overexpression of HOXA10 is required to generate AML in primary recipient mice, but is not essential for maintenance of the leukemia. Transplantation of AML to secondary recipients showed that in established leukemias, ∼80% of the leukemia-initiating cells (LICs) in bone marrow stopped proliferating upon withdrawal of HOXA10 overexpression. However, the population of LICs in primary recipients is heterogeneous, as ∼20% of the LICs induce leukemia in secondary recipients despite elimination of HOXA10-induced overexpression. Intrinsic genetic activation of several proto-oncogenes was observed in leukemic cells resistant to inactivation of the initial transformation event. Interestingly, high levels of the adhesion molecule CD44 on leukemic cells are essential to generate leukemia after removal of the primary event. This suggests that extrinsic niche-dependent factors are also involved in the host-dependent outgrowth of leukemias after withdrawal of HOXA10 overexpression event that initiates the leukemia.
61 citations
TL;DR: Findings reveal a major role for Smad4 in the negative regulation of leukemia initiation and maintenance induced by HOXA9/NUP98-HOXA 9 and provide strong evidence that antagonizing Smad 4 stabilization by these oncoproteins might be a promising novel therapeutic approach in leukemia.
34 citations
TL;DR: The hematopoietic stem cells (HSC) is the prototype organ-regenerating stem cell (SC) and by far the most studied type of SC in the body as discussed by the authors.
Abstract: The hematopoietic stem cell (HSC) is the prototype organ-regenerating stem cell (SC), and by far the most studied type of SC in the body. Currently, HSC-based therapy is the only routinely used SC therapy; however, advances in the field of embryonic SCs and induced pluripotent SCs may change this situation. Interest into in vitro generation of HSCs, including signals for HSC expansion and differentiation from these more primitive SCs, as well as advances in other organ-specific SCs, in particular the intestine, provide promising new applications for SC therapies. Here, we review the basic principles of different SC systems, and on the basis of the experience with HSC-based SC therapy, provide recommendations for clinical application of emerging SC technologies.
23 citations
TL;DR: Cripto/GRP78 signaling is important to sustain HSCs in the hypoxic niche and several glycolytic metabolism-related proteins were up-regulated and/or phosphorylated by Cripto treatment, e.g. Pyruvate kinase, Phosphoglycerate Kinase 1, and Triosephosphate isomerase.
7 citations
TL;DR: A key role of p53 activation in RPS19-deficient DBA is demonstrated and the preliminary data supports the role of L-leucine as a therapeutic agent in the treatment of DBA and suggests that p53-independent pathways may contribute towards phenotype upon severe RPS 19 deficiency.
4 citations
01 Jan 2011
TL;DR: The basic principles of different SC systems are reviewed, and on the basis of the experience with HSC-based SC therapy, recommendations for clinical application of emerging SC technologies are provided.
Abstract: The hematopoietic stem cell (HSC) is the prototype organ-regenerating stem cell (SC), and by far the most studied typeof SC in the body. Currently, HSC-based therapy is the onlyroutinely used SC therapy; however, advances in the field ofembryonic SCs and induced pluripotent SCs may change thissituation. Interest into in vitro generation of HSCs, includingsignals for HSC expansion and differentiation from these moreprimitive SCs, as well as advances in other organ-specific SCs,in particular the intestine, provide promising new applicationsfor SC therapies. Here, we review the basic principles ofdifferent SC systems, and on the basis of the experience withHSC-based SC therapy, provide recommendations for clinicalapplication of emerging SC technologies.Leukemia (2011) 25, 1095–1102; doi:10.1038/leu.2011.52;published online 29 April 2011Keywords: stem cell; iPS; gene therapy; embryonic stem cell;transplantation
1 citations
TL;DR: Mice with a mutated Erg allele and a normal allele are studied and it is found that normal steady state hematopoiesis can be maintained in these mice whereas stress-induced self-renewal ofhematopoietic stem cells is impaired.