| 1. |
- Brynjólfsson, Siggeir Fannar, et al.
(författare)
-
Long-lived plasma cells in human bone marrow can be either CD191(+) or CD19(-)
- 2017
-
Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 1:13, s. 835-838
-
Tidskriftsartikel (refereegranskat)abstract
- Long-lived plasma cells secreting vaccinia-specific antibodies are detected in human bone marrow >35 years after the eradication of smallpox. Long-lived plasma cells secreting vaccinia-specific antibodies are still able to express the B-lymphocyte antigen CD19.
|
|
| 2. |
- Eriksson, Mia, et al.
(författare)
-
Agonistic targeting of TLR1/TLR2 induces p38 MAPK-dependent apoptosis and NFκB-dependent differentiation of AML cells
- 2017
-
Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 1:23, s. 2046-2057
-
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.
|
|
| 3. |
- Halvarsson, Britt-Marie, et al.
(författare)
-
Direct evidence for a polygenic etiology in familial multiple myeloma
- 2017
-
Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 1:10, s. 619-623
-
Tidskriftsartikel (refereegranskat)abstract
- Although common risk alleles for multiple myeloma have been identified, their contribution to familial MM is unknown. We demonstrate an enrichment of common MM risk alleles in familial cases, providing the first direct evidence for a polygenic contribution.
|
|
| 4. |
- Hollander, Peter, et al.
(författare)
-
High proportions of PD-1+ and PD-L1+ leukocytes in classical Hodgkin lymphoma microenvironment are associated with inferior outcome
- 2017
-
Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 1:18, s. 1427-1439
-
Tidskriftsartikel (refereegranskat)abstract
- Immune checkpoint inhibition targeting the programmed death receptor (PD)-1 pathway is a novel treatment approach in relapsed and refractory classical Hodgkin lymphoma (cHL). Identifying patients with a high risk of treatment failure could support the use of PD-1 inhibitors as front-line treatment. Our aim was to investigate the prognostic impact of PD-1, programmed death-ligand 1 (PD-L1), and PD-L2 in the tumor microenvironment in diagnostic biopsies of patients with cHL. Patients from Denmark and Sweden, diagnosed between 1990 and 2007 and ages 15 to 86 years, were included. Tissue microarray samples were available from 387 patients. Immunohistochemistry was used to detect PD-1, PD-L1, and PD-L2, and the proportions of positive cells were calculated. Event-free survival (EFS; time to treatment failure) and overall survival (OS) were analyzed using Cox proportional hazards regression. High proportions of both PD-1(+) (hazard ratio [HR], 1.77; 95% confidence interval [CI], 1.10-2.86) and PD-L1(+) (HR 5 1.89; 95% CI, 1.08-3.30) leukocytes in the microenvironment were associated with inferior EFS in a multivariate analysis (adjusted for white blood cell count >15 x 10(9)/L, hemoglobin <105 g/L, albumin <40 g/L, B symptoms, extranodal involvement, stage, bulky tumor, nodular sclerosis subtype, Epstein-Barr virus status, lymphocyte count <0.6 x 10(9)/L, sex, and country). A high proportion of PD-L1(+) leukocytes was also associated with inferior OS in a multivariate analysis (HR, 3.46; 95% CI, 1.15-10.37). This is the first study to show a correlation after multivariate analysis between inferior outcome in cHL and a high proportion of both PD-1(+) and PD-L1(+) leukocytes in the tumor microenvironment.
|
|
| 5. |
|
|
| 6. |
- Karvonen, H, et al.
(författare)
-
Crosstalk between ROR1 and BCR pathways defines novel treatment strategies in mantle cell lymphoma
- 2017
-
Ingår i: Blood advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 1:24, s. 2257-2268
-
Tidskriftsartikel (refereegranskat)abstract
- Targeting ROR1 downregulates NF-κB p65 expression and sensitizes MCL cells to BCR- or Bcl-2–targeted drugs. Inhibition of BCR signaling by BTK-specific inhibitors such as ibrutinib impairs ROR1 levels and consecutively ROR1-targeted therapies.
|
|
| 7. |
- Mailankody, S, et al.
(författare)
-
Baseline mutational patterns and sustained MRD negativity in patients with high-risk smoldering myeloma
- 2017
-
Ingår i: Blood advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 1:22, s. 1911-1918
-
Tidskriftsartikel (refereegranskat)abstract
- Patients with high-risk smoldering myeloma treated with 3-drug combinations have deep and durable responses with 63% MRD negativity. Baseline mutations in high-risk smoldering myeloma and newly diagnosed myeloma are different, which suggests treatment-responsive biology.
|
|
| 8. |
- Meinderts, Sanne M., et al.
(författare)
-
Human and murine splenic neutrophils are potent phagocytes of IgG-opsonized red blood cells
- 2017
-
Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 1:14, s. 875-886
-
Tidskriftsartikel (refereegranskat)abstract
- Red blood cell (RBC) clearance is known to occur primarily in the spleen, and is presumed to be executed by red pulp macrophages. Erythrophagocytosis in the spleen takes place as part of the homeostatic turnover of RBCs to remove old RBCs. It can be strongly promoted by immunoglobulin G (IgG) opsonization of RBCs, a condition that can occur as a consequence of autoantibody or alloantibody formation. The purpose of our study was to investigate which phagocytes are involved in IgG-mediated RBC clearance in the human spleen. We developed a highly specific in vitro assay to monitor RBC phagocytosis in total human splenocytes. Surprisingly, we have found that whereas homeostatic clearance of RBCs is primarily a task for splenic macrophages, neutrophils and, to a lesser extent, also monocytes can be a major factor in clearance of IgG-opsonized RBCs. Erythrophagocytosis by neutrophils is strongly dependent on the degree of opsonization of the RBCs. Additionally, the process is enhanced after blocking the "do not eat me" signal CD47 on the opsonized RBCs, which binds signal regulatory protein a, a myeloid inhibitory receptor that restricts phagocytosis. Moreover, RBCs isolated from autoimmune hemolytic anemia patients, opsonized by auto-IgGs, were shown to be readily phagocytosed by neutrophils. Finally, priming of neutrophils by inflammatory mediators such as tumor necrosis factor a and lipopolysaccharide further increases the magnitude of erythrophagocytosis. Collectively, our data suggest that neutrophils contribute significantly to the phagocytosis of antibody-opsonized RBCs, especially under inflammatory conditions. This indicates a hereto unanticipated contribution of neutrophils in RBC phagocytosis, especially under pathological conditions such as alloimmunization or autoimmunization.
|
|
| 9. |
|
|
| 10. |
- Snowden, John A., et al.
(författare)
-
Evolution, trends, outcomes, and economics of hematopoietic stem cell transplantation in severe autoimmune diseases
- 2017
-
Ingår i: Blood Advances. - : AMER SOC HEMATOLOGY. - 2473-9529 .- 2473-9537. ; 1:27, s. 2742-2755
-
Tidskriftsartikel (refereegranskat)abstract
- Hematopoietic stem cell transplantation (HSCT) has evolved for >20 years as a specific treatment of patients with autoimmune disease (AD). Using European Society for Blood and Marrow Transplantation registry data, we summarized trends and identified factors influencing activity and outcomes in patients with AD undergoing first autologous HSCT (n = 1951; median age, 37 years [3-76]) and allogeneic HSCT (n = 105; median age, 12 years [<1-62]) in 247 centers in 40 countries from 1994 to 2015. Predominant countries of activity were Italy, Germany, Sweden, the United Kingdom, The Netherlands, Spain, France, and Australia. National activity correlated with the Human Development Index (P = .006). For autologous HSCT, outcomes varied significantly between diseases. There was chronological improvement in progression-free survival (PFS, P < 10(-5)), relapse/ progression (P < 10(-5)), and nonrelapse mortality (P = .01). Health care expenditure was associated with improved outcomes in systemic sclerosis and multiple sclerosis (MS). On multivariate analysis selecting adults for MS, systemic sclerosis, and Crohn disease, better PFSwas associated with experience (>= 23 transplants for AD, P = .001), learning (time from first HSCT for AD >= 6 years, P = .01), and Joint Accreditation Committee of the International Society for Cellular Therapy and European Society for Blood and Marrow Transplantation accreditation status (P = .02). Despite improved survival over time (P = .02), allogeneic HSCT use remained low and largely restricted to pediatric practice. Autologous HSCT has evolved into a treatment modality to be considered alongside other modern therapies in severe AD. Center experience, accreditation, interspecialty networking, and national socioeconomic factors are relevant for health service delivery of HSCT in AD.
|
|
