| 1. |
- Sandén, Carl, et al.
(författare)
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Clonal competition within complex evolutionary hierarchies shapes AML over time
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Clonal heterogeneity and evolution has major implications for disease progression and relapse in acute myeloid leukemia (AML). To model clonal dynamics in vivo, we serially transplanted 23 AML cases to immunodeficient mice and followed clonal composition for up to 15 months by whole-exome sequencing of 84 xenografts across two generations. We demonstrate vast changes in clonality that both progress and reverse over time, and define five patterns of clonal dynamics: Monoclonal, Stable, Loss, Expansion and Burst. We also show that subclonal expansion in vivo correlates with a more adverse prognosis. Furthermore, clonal expansion enabled detection of very rare clones with AML driver mutations that were undetectable by sequencing at diagnosis, demonstrating that the vast majority of AML cases harbor multiple clones already at diagnosis. Finally, the rise and fall of related clones enabled deconstruction of the complex evolutionary hierarchies of the clones that compete to shape AML over time.
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| 2. |
- Ågerstam, Helena, et al.
(författare)
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Antibodies targeting human IL1RAP (IL1R3) show therapeutic effects in xenograft models of acute myeloid leukemia.
- 2015
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 112:34, s. 10786-10791
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Tidskriftsartikel (refereegranskat)abstract
- Acute myeloid leukemia (AML) is associated with a poor survival rate, and there is an urgent need for novel and more efficient therapies, ideally targeting AML stem cells that are essential for maintaining the disease. The interleukin 1 receptor accessory protein (IL1RAP; IL1R3) is expressed on candidate leukemic stem cells in the majority of AML patients, but not on normal hematopoietic stem cells. We show here that monoclonal antibodies targeting IL1RAP have strong antileukemic effects in xenograft models of human AML. We demonstrate that effector-cell-mediated killing is essential for the observed therapeutic effects and that natural killer cells constitute a critical human effector cell type. Because IL-1 signaling is important for the growth of AML cells, we generated an IL1RAP-targeting antibody capable of blocking IL-1 signaling and show that this antibody suppresses the proliferation of primary human AML cells. Hence, IL1RAP can be efficiently targeted with an anti-IL1RAP antibody capable of both achieving antibody-dependent cellular cytotoxicity and blocking of IL-1 signaling as modes of action. Collectively, these results provide important evidence in support of IL1RAP as a target for antibody-based treatment of AML.
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| 3. |
- Ågerstam, Helena, et al.
(författare)
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IL1RAP antibodies block IL-1-induced expansion of candidate CML stem cells and mediate cell killing in xenograft models.
- 2016
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 128:23, s. 2683-2693
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Tidskriftsartikel (refereegranskat)abstract
- Chronic myeloid leukemia (CML) is currently treated with tyrosine kinase inhibitors, but these do not effectively eliminate the CML stem cells. As a consequence, CML stem cells persist and cause relapse in most patients upon drug discontinuation. Furthermore, no effective therapy exists for the advanced stages of the disease. Interleukin-1 receptor accessory protein (IL1RAP; IL1R3) is a coreceptor of interleukin-1 receptor type 1 and has been found upregulated on CML stem cells. Here, we show that primitive (CD34(+)CD38(-)) CML cells, in contrast to corresponding normal cells, express a functional interleukin-1 (IL-1) receptor complex and respond with NF-κB activation and marked proliferation in response to IL-1. IL1RAP antibodies that inhibit IL-1 signaling could block these effects. In vivo administration of IL1RAP antibodies in mice transplanted with chronic and blast phase CML cells resulted in therapeutic effects mediated by murine effector cells. These results provide novel insights into the role of IL1RAP in CML and a strong rationale for the development of an IL1RAP antibody therapy to target residual CML stem cells.
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| 4. |
- Askmyr, Maria, et al.
(författare)
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Modeling chronic myeloid leukemia in immunodeficient mice reveals expansion of aberrant mast cells and accumulation of pre-B cells.
- 2014
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Ingår i: Blood Cancer Journal. - : Springer Science and Business Media LLC. - 2044-5385. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm that, if not treated, will progress into blast crisis (BC) of either myeloid or B lymphoid phenotype. The BCR-ABL1 fusion gene, encoding a constitutively active tyrosine kinase, is thought to be sufficient to cause chronic phase (CP) CML, whereas additional genetic lesions are needed for progression into CML BC. To generate a humanized CML model, we retrovirally expressed BCR-ABL1 in the cord blood CD34(+) cells and transplanted these into NOD-SCID (non-obese diabetic/severe-combined immunodeficient) interleukin-2-receptor γ-deficient mice. In primary mice, BCR-ABL1 expression induced an inflammatory-like state in the bone marrow and spleen, and mast cells were the only myeloid lineage specifically expanded by BCR-ABL1. Upon secondary transplantation, the pronounced inflammatory phenotype was lost and mainly human mast cells and macrophages were found in the bone marrow. Moreover, a striking block at the pre-B-cell stage was observed in primary mice, resulting in an accumulation of pre-B cells. A similar block in B-cell differentiation could be confirmed in primary cells from CML patients. Hence, this humanized mouse model of CML reveals previously unexplored features of CP CML and should be useful for further studies to understand the disease pathogenesis of CML.
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| 5. |
- Askmyr, Maria, et al.
(författare)
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Transgenic expression of human cytokines in immunodeficient mice does not facilitate myeloid expansion of BCR-ABL1 transduced human cord blood cells
- 2017
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:10
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Tidskriftsartikel (refereegranskat)abstract
- Several attempts have been made to model chronic myeloid leukemia (CML) in a xenograft setting but expansion of human myeloid cells in immunodeficient mice has proven difficult to achieve. Lack of cross-reacting cytokines in the microenvironment of the mice has been proposed as a potential reason. In this study we have used NOD/SCID IL2–receptor gamma deficient mice expressing human SCF, IL-3 and GM-CSF (NSGS mice), that should be superior in supporting human, and particularly, myeloid cell engraftment, to expand BCR-ABL1 expressing human cells in order to model CML. NSGS mice transplanted with BCR-ABL1 expressing cells became anemic and had to be sacrificed due to illness, however, this was not accompanied by an expansion of human myeloid cells but rather we observed a massive expansion of human T-cells and macrophages/histiocytes. Importantly, control human cells without BCR-ABL1 expression elicited a similar reaction, although with a slight delay of disease induction, suggesting that while BCR-ABL1 contributes to the inflammatory reaction, the presence of normal human hematopoietic cells is detrimental for NSGS mice.
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| 6. |
- Burroughs, Brady, 1970-
(författare)
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Ahmed for Architecture Students
- 2019
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Calling all architectural feminist killjoys!Academic publishers Routledge produce a series called ‘Thinkers for Architects’, introducing philosophical and theoretical ideas to an architectural audience. The fifteen current titles include the usual suspects, Bourdieu, Foucault, Derrida, Merleau-Ponty, with one female thinker, Irigaray. In this publication, we begin to suggest a new series and to outline a book they should have commissioned, ‘Ahmed for Architecture Students’, as a critical revision and architectural killjoy. Based on key texts spanning queer feminist Sara Ahmed’s career as a critical scholar, this master’s seminar course has collectively produced a fanzine to introduce Ahmed’s ideas and concepts, along with possible connections to the discipline and culture of architecture, making them accessible to architecture students and practitioners.We have provided three digital files: 1) Digital Spreads - Fanzine, for reading directly on a digital device. 2) Print version - Fanzine Inlay, for printing your own hard copy of the inner pages. 3) Print version - Fanzine Cover, for printing your own hard copy of the outer cover. (On the back of the cover, you will find DIY Instructions to assemble your own fanzine.)We think the fanzine is ‘amazingly awesome’ and encourage you to share the link to the DiVA database for download, so we have an idea of how many people find our publication. And why not organize a ‘DIY Fanzine workshop’, to make and share the fanzine with friends? Bake a lemon poppy seed cake for starters and be sure to use recycled paper!
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| 7. |
- Castro, Vasco, et al.
(författare)
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NMR investigations of interactions between anesthetics and lipid bilayers
- 2008
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Ingår i: Biochimica et Biophysica Acta - Biomembranes. - : ELSEVIER SCIENCE BV. - 0005-2736 .- 1879-2642. ; 1178:11, s. 2604-2611
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Tidskriftsartikel (refereegranskat)abstract
- Interactions between anesthetics (lidocaine and short chain alcohols) and lipid membranes formed by dimyristoylphosphatidylcholine (DMPC) were studied using NMR spectroscopy. The orientational order of lidocaine was investigated using deuterium NMR on a selectively labelled compound whereas segmental ordering in the lipids was probed by two-dimensional 1H–13C separated local field experiments under magic-angle spinning conditions. In addition, trajectories generated in molecular dynamics (MD) computer simulations were used for interpretation of the experimental results. Separate simulations were carried out with charged and uncharged lidocaine molecules. Reasonable agreement between experimental dipolar interactions and the calculated counterparts was observed. Our results clearly show that charged lidocaine affects significantly the lipid headgroup. In particular the ordering of the lipids is increased accompanied by drastic changes in the orientation of the P–N vector in the choline group.
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| 8. |
- Chapellier, Marion, et al.
(författare)
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Arrayed molecular barcoding identifies TNFSF13 as a positive regulator of acute myeloid leukemia-initiating cells
- 2019
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 1592-8721 .- 0390-6078. ; 104:10, s. 2006-2016
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Tidskriftsartikel (refereegranskat)abstract
- Dysregulation of cytokines in the bone marrow microenvironment promotes acute myeloid leukemia cell growth. Due to the complexity and low throughput of in vivo stem-cell based assays, studying the role of cytokines in the bone marrow niche in a screening setting is challenging. Herein, we developed an ex vivo cytokine screen using 11 arrayed molecular barcodes, allowing for a competitive in vivo readout of leukemia-initiating capacity. With this approach, we assessed the effect of 114 murine cytokines on MLL-AF9 acute myeloid leukemia mouse cells and identified the tumor necrosis factor ligand superfamily member 13 (TNFSF13) as a positive regulator of leukemia-initiating cells. By using Tnfsf13-/- recipient mice, we confirmed that TNFSF13 supports leukemia-initiation also under physiological conditions. TNFSF13 was secreted by normal myeloid cells but not by leukemia mouse cells, suggesting that mature myeloid bone marrow cells support leukemia cells by secreting TNFSF13. TNFSF13 supported leukemia cell proliferation in an NF-κB-dependent manner by binding TNFRSF17 and suppressed apoptosis. Moreover, TNFSF13 supported the growth and survival of several human myeloid leukemia cell lines, demonstrating that our findings translate to human disease. Taken together, using arrayed molecular barcoding, we identified a previously unrecognized role of TNFSF13 as a positive regulator of acute myeloid leukemia-initiating cells. The arrayed barcoded screening methodology is not limited to cytokines and leukemia, but can be extended to other types of ex vivo screens, where a multiplexed in vivo read-out of stem cell functionality is needed.
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| 9. |
- Eriksson, Mia, et al.
(författare)
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Agonistic targeting of TLR1/TLR2 induces p38 MAPK-dependent apoptosis and NFκB-dependent differentiation of AML cells
- 2017
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 1:23, s. 2046-2057
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Tidskriftsartikel (refereegranskat)abstract
- Acute myeloid leukemia (AML) is associated with poor survival, and there is a strong need to identify disease vulnerabilities that might reveal new treatment opportunities. Here, we found that Toll-like receptor 1 (TLR1) and TLR2 are upregulated on primary AML CD34+CD38-cells relative to corresponding normal bone marrow cells. Activating the TLR1/TLR2 complex by the agonist Pam3CSK4 inMLL-AF9-driven human AML resulted in induction of apoptosis by p38 MAPK-dependent activation of Caspase 3 and myeloid differentiation in a NFκB-dependent manner. By using murineTrp53 -/- MLL-AF9AML cells, we demonstrate that p53 is dispensable for Pam3CSK4-induced apoptosis and differentiation. Moreover, murineAML1-ETO9a-driven AML cells also were forced into apoptosis and differentiation on TLR1/TLR2 activation, demonstrating that the antileukemic effects observed were not confined toMLL-rearranged AML. We further evaluated whether Pam3CSK4 would exhibit selective antileukemic effects. Ex vivo Pam3CSK4 treatment inhibited murine and human leukemia-initiating cells, whereas murine normal hematopoietic stem and progenitor cells (HSPCs) were relatively less affected. Consistent with these findings, primary human AML cells across several genetic subtypes of AML were more vulnerable for TLR1/TLR2 activation relative to normal human HSPCs. In theMLL-AF9AML mouse model, treatment with Pam3CSK4 provided proof of concept for in vivo therapeutic efficacy. Our results demonstrate that TLR1 and TLR2 are upregulated on primitive AML cells and that agonistic targeting of TLR1/TLR2 forces AML cells into apoptosis by p38 MAPK-dependent activation of Caspase 3, and differentiation by activating NFκB, thus revealing a new putative strategy for therapeutically targeting AML cells.
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| 10. |
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