| 1. |
- Engert, Andreas, et al.
(författare)
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The European Hematology Association Roadmap for European Hematology Research : a consensus document
- 2016
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Ingår i: Haematologica. - Pavia, Italy : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 101:2, s. 115-208
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Tidskriftsartikel (refereegranskat)abstract
- The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at (sic)23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine 'sections' in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients.
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| 2. |
- Li, Hongzhe, et al.
(författare)
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Early growth response 1 regulates hematopoietic support and proliferation in human primary bone marrow stromal cells
- 2020
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 1592-8721 .- 0390-6078. ; 105:5, s. 1206-1215
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Tidskriftsartikel (refereegranskat)abstract
- Human bone marrow stromal cells are key elements of the hematopoietic environment and they play a central role in bone and bone marrow physiology. However, how key stromal cell functions are regulated is largely unknown. We analyzed the role of the immediate early response transcription factor EGR1 as key stromal cell regulator and found that EGR1 was highly expressed in prospectively-isolated primary bone marrow stromal cells, downregulated upon culture, and low in non-colony-forming CD45neg stromal cells. Furthermore, EGR1 expression was lower in proliferative regenerating adult and fetal primary cells compared to adult steady-state bone marrow stromal cells. Overexpression of EGR1 in stromal cells induced potent hematopoietic stroma support as indicated by an increased production of transplantable CD34+CD90+ hematopoietic stem cells in expansion co-cultures. The improvement of bone marrow stroma support function was mediated by increased expression of hematopoietic supporting genes, such as VCAM1 and CCL28. Furthermore, EGR1 overexpression markedly decreased stromal cell proliferation whereas EGR1 knockdown caused the opposite effects. These findings thus show that EGR1 is a key stromal transcription factor with a dual role in regulating proliferation and hematopoietic stroma support function that is controlling a genetic program to coordinate the specific functions of bone marrow stromal cells in their different biological contexts.
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| 3. |
- Österroos, Albin, 1988-
(författare)
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Improving prognostication and treatment choices for patients with AML
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The treatment landscape of the aggressive haematological malignancy acute myeloid leukaemia (AML) has expanded but the prognosis is still unsatisfactory poor. Here, we aimed at improving prognostication and treatment choices in AML by addressing current clinical obstacles to successful AML treatment.Acute promyelocytic leukaemia (APL) is an AML subset characterised by a high rate of early death (ED). In Paper I, we developed a novel risk score for ED in APL. We identified three risk groups for ED based on regression analyses on first a training cohort from the population-based Swedish AML Registry (n=301) and later an external validation cohort from a hospital-based registry (n=129). The presented risk score included age, platelets and white blood cell (WBC) count. Importantly, already sub-normal to normal WBC counts conferred higher risks of ED.Molecular studies of elderly AML patients are sparse. In Paper II, we focused on patients ≥65 years to investigate the prognostic effect of molecular markers and to propose an algorithm for response to intensive chemotherapy (IC) in this patient group. We combined clinical data with targeted DNA- and RNA-sequencing of 182 patients. Notably, we identified and externally validated three risk categories for complete remission achievement after IC based on mutational status of TP53 and gene expression levels of ZBTB7A and EEPD1.Hypomethylating agents (HMAs) constitute a backbone for AML patients ineligible for IC. There are limited studies on their effectiveness in the real-world setting. In Paper III, we compared the utility of HMAs against IC and palliative care in all AML patients ≥60 years in Sweden (n=3135) during 2008-2018. Propensity score matching in this population-based cohort showed that HMAs are as effective as IC upfront when patient characteristics were balanced. Additionally, predictive factors for overall survival in HMA treated patients were different to IC treated patients.The HMA azacitidine combined with venetoclax is the current frontline option to AML patients unfit for IC. Few studies have addressed how this synergism arises. In Paper IV, we characterised the epigenetic and transcriptomic effects of azacitidine-venetoclax in vitro and elucidated potential survival/resistance mechanisms in AML blasts including the serine synthesis pathway and NTRK signaling. Furthermore, we utilised obtained RNA-seq data and in silico predictions to propose add-ons to azacitidine-venetoclax to further strengthen the synergy.In summary, the research presented herein contributes to improved personalised medicine in AML via real-world data, risk stratification algorithms and insights into potential novel therapeutic approaches.
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