Genetic variants in C5 and poor response to eculizumab Nishimura, Jun-ichi; Yamamoto, Masaki; Hayashi, Shin ...
New England journal of medicine/The New England journal of medicine,
02/2014, Volume:
370, Issue:
7
Journal Article
Peer reviewed
Open access
Eculizumab is a humanized monoclonal antibody that targets complement protein C5 and inhibits terminal complement-mediated hemolysis associated with paroxysmal nocturnal hemoglobinuria (PNH). The ...molecular basis for the poor response to eculizumab in a small population of Japanese patients is unclear.
We assessed the sequences of the gene encoding C5 in patients with PNH who had either a good or poor response to eculizumab. We also evaluated the functional properties of C5 as it was encoded in these patients.
Of 345 Japanese patients with PNH who received eculizumab, 11 patients had a poor response. All 11 had a single missense C5 heterozygous mutation, c.2654G → A, which predicts the polymorphism p.Arg885His. The prevalence of this mutation among the patients with PNH (3.2%) was similar to that among healthy Japanese persons (3.5%). This polymorphism was also identified in a Han Chinese population. A patient in Argentina of Asian ancestry who had a poor response had a very similar mutation, c.2653C → T, which predicts p.Arg885Cys. Nonmutant and mutant C5 both caused hemolysis in vitro, but only nonmutant C5 bound to and was blocked by eculizumab. In vitro hemolysis due to nonmutant and mutant C5 was completely blocked with the use of N19-8, a monoclonal antibody that binds to a different site on C5 than does eculizumab.
The functional capacity of C5 variants with mutations at Arg885, together with their failure to undergo blockade by eculizumab, account for the poor response to this agent in patients who carry these mutations. (Funded by Alexion Pharmaceuticals and the Ministry of Health, Labor, and Welfare of Japan.).
Recurrent inactivating mutations have been identified in various hematological malignancies in the X-linked
gene encoding BCL6 corepressor (BCOR); however, its tumor suppressor function remains ...largely uncharacterized. We generated mice missing
exon 4, expressing a variant BCOR lacking the BCL6-binding domain. Although the deletion of exon 4 in male mice (
) compromised the repopulating capacity of hematopoietic stem cells,
thymocytes had augmented proliferative capacity in culture and showed a strong propensity to induce acute T-cell lymphoblastic leukemia (T-ALL), mostly in a Notch-dependent manner.
, one of the critical NOTCH1 targets in T-ALL, was highly up-regulated in
T-ALL cells. Chromatin immunoprecipitation/DNA sequencing analysis revealed that BCOR was recruited to the
promoter and restrained its activation in thymocytes. BCOR also targeted other NOTCH1 targets and potentially antagonized their transcriptional activation.
-deficient thymocytes behaved in a manner similar to
thymocytes. Our results provide the first evidence of a tumor suppressor role for BCOR in the pathogenesis of T lymphocyte malignancies.
Radiation therapy is one of the major treatment modalities for patients with cancers. However, ionizing radiation (IR) damages not only cancer cells but also the surrounding vascular endothelial ...cells (ECs). Hippo pathway effector genes Yap1 and Taz are the two transcriptional coactivators that have crucial roles in tissue homeostasis and vascular integrity in various organs. However, their function in adult ECs at the steady state and after IR is poorly understood. Here, we report sex- and context-dependent roles of endothelial YAP1/TAZ in maintaining vascular integrity and organismal survival. EC-specific Yap1/Taz deletion compromised systemic vascular integrity, resulting in lethal circulation failure preferentially in male mice. Furthermore, EC-specific Yap1/Taz deletion induced acute lethality upon sublethal IR that was closely associated with exacerbated systemic vascular dysfunction and circulation failure. Consistent with these findings, RNA-seq analysis revealed downregulation of tight junction genes in Yap1/Taz-deleted ECs. Collectively, our findings highlight the importance of endothelial YAP1/TAZ for maintaining adult vascular function, which may provide clinical implications for preventing organ injury after radiation therapy.
•Yap1/Taz deletion in ECs causes vascular dysfunction and lethality in male mice.•IR activates Yap1/Taz in EC to maintain vascular integrity and mouse survival.•Yap1/Taz deletion disrupts gene expression of tight junction components.
Purpose
Bloodstream infection (BSI) is a major complication of allogeneic hematopoietic stem-cell transplantation (allo-SCT). There are several causes of BSI; in particular, severe oral mucositis ...(OM) can induce BSI due to coagulase-negative staphylococci (CoNS). The OM severity may be reduced with intensive oral care. Thus, we evaluated whether the type of oral care affects the BSI incidence eventually.
Method
We performed retrospective analysis on 206 recipients who underwent allo-SCT from 2006 to 2017 at our institute. Intensive oral care by a dental specialist was performed for 111 recipients (intensive-care group) and self-oral care was performed by 95 recipients (self-care group). Incidence of BSI was assessed by type of the oral care, before neutrophil engraftment (pre-E-BSI) and after neutrophil engraftment (post-E-BSI) period until 180 days after allo-SCT.
Result
A total of 112 BSI occurred in 90 of the 206 recipients and 120 bacteria were identified, with CoNS being the most prevalent. There was no significant difference in the incidence of pre-E-BSI between the self-care and intensive-care groups (30.8% and 30.6%, respectively;
P
= 0.508). Meanwhile, the incidence of post-E-BSI was significantly lower in the intensive-care group than in the self-care group (14.3% and 28.6%;
P
= 0.008). In addition, the intensive-care group had significantly lower incidence of post-E-BSI with CoNS than the self-care group (8.5% and 21.5%, respectively;
P
= 0.009).
Conclusion
Intensive oral care through the period of allo-HCT can significantly reduce the post-E-BSI occurrence, especially due to CoNS.
Donor T cell activation, proliferation, differentiation, and migration are the major steps involved in graft-versus-host disease (GVHD) development following bone marrow transplantation. Chondroitin ...sulfate (CS) proteoglycan is a major component of the extracellular matrix and causes immune modulation by interacting with cell growth factors and inducing cell adhesion. However, its precise effects on immune function are unclear than those of other proteoglycan families. Thus, we investigated the significance of CS within donor cells in acute GVHD development utilizing CSGalNAc T1-knockout (T1KO) mice. To determine the effects of T1KO, the mice underwent allogenic bone marrow transplantation from major histocompatibility complex-mismatched donors. While transplantation resulted in hepatic GVHD with inflammatory cell infiltration of both CD4
and CD8
effector memory T cells, transplantation in T1KO-donors showed milder cell infiltration and improved survival with fewer splenic effector T cells. In vitro T-cell analyses showed that the ratio of effector memory T cells was significantly lower via phorbol myristate acetate/ionomycin stimulation. Moreover, quantitative PCR analyses showed significantly less production of inflammatory cytokines, such as IFN-γ and CCL-2, in splenocytes of T1KO mice. These results suggest that reduction of CS in donor blood cells may suppress the severity of acute GVHD after hematopoietic stem cell transplantation.
Introduction
Chromosome analysis is necessary for the risk classification of acute myeloid leukemia (AML). Marker chromosome (MC) is a fragmented chromosome whose origin cannot be identified from ...other chromosomes and originates from marked genomic instability. Although AML with MC (MC+) has a poor prognosis even after intensive chemotherapy, its influence on the outcome after allogeneic hematopoietic stem cell transplantation (allo‐HSCT) is unclear.
Objective and Methods
We retrospectively analyzed 162 AML patients after allo‐HSCT. To evaluate the significance of MC, we compared it with other chromosomal abnormalities.
Result
Marker chromosome was detected in 14 (8.6%, MC+) patients (vs MC−, n = 158). The 2‐year overall survival (OS) in MC+ vs MC− was 26.8% vs 62.2% (P = .0098). The 2‐year cumulative incidence of relapse (CIR) in MC+ vs MC− was 80.4% vs 35.5% (P = .0004). Among adverse‐risk AML (AD‐AML, n = 36), AD‐AML/MC+ (n = 11) demonstrated a poorer 2‐year OS (9.1%, vs AD‐AML/MC− n = 25, 58.3%, P = .0031) and higher 2‐year CIR (89.6%, vs AD‐AML/MC− 44.7%, P = .002). In multivariate analysis, MC (HR 3.08, 95% CI; 1.02‐9.29, P = .046) and HCT‐CI (HR 3.23, 95% CI; 1.00‐10.4, P = .049) were independent risk factors for CIR among AD‐AML.
Conclusion
Our study suggests MC as a new independent factor for chromosome risk classification to further classify AD‐AML.
The bone marrow (BM) microenvironment, known as the BM niche, regulates hematopoiesis but is also affected by interactions with hematopoietic cells. Recent evidence indicates that extracellular ...matrix components are involved in these interactions. Chondroitin sulfate (CS), a glycosaminoglycan, is a major component of the extracellular matrix; however, it is not known whether CS has a physiological role in hematopoiesis. Here, we analyzed the functions of CS in hematopoietic and niche cells. CSGalNAcT1, which encodes CS N-acetylgalactosaminyltransferase-1 (T1), a key enzyme in CS biosynthesis, was highly expressed in hematopoietic stem and progenitor cells (HSPCs) and endothelial cells (ECs), but not in mesenchymal stromal cells (MSCs) in BM. In T1 knockout (T1KO) mice, a greater number of HSPCs existed compared with the wild-type (WT), but HSPCs from T1KO mice showed significantly impaired repopulation in WT recipient mice on serial transplantation. RNA sequence analysis revealed the activation of IFN-α/β signaling and endoplasmic reticulum stress in T1KO HSPCs. In contrast, the number of WT HSPCs repopulated in T1KO recipient mice was larger than that in WT recipient mice after serial transplantation, indicating that the T1KO niche supports repopulation of HSPCs better than the WT niche. There was no obvious difference in the distribution of vasculature and MSCs between WT and T1KO BM, suggesting that CS loss alters vascular niche functions without affecting its structure. Our results revealed distinct roles of CS in hematopoietic cells and BM niche, indicating that crosstalk between these components is important to maintain homeostasis in BM.
Pretransplant measurable residual disease (MRD) has been shown to be associated with relapse incidence following allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML). ...However, it remains less clear whether pretransplant MRD status affects transplant outcomes in core binding factor AML (CBF-AML). We retrospectively evaluated the effect of pretransplant MRD, which was measured by a polymerase chain reaction of RUNX1-RUNX1T1 or CBFB-MYH11 fusion transcripts, on transplant outcomes for a cohort of 959 adult patients with t(8;21) or inv(16) AML treated by allogeneic HCT during complete remission (CR), between 2000 and 2018. Multivariate analysis showed the absence of pretransplant MRD was significantly associated with lower relapse (hazard ratio HR, 0.46; P < 0.001), treatment failure (HR, 0.66; P = 0.004), and overall mortality (HR, 0.72; P = 0.037) among patients with t(8;21). However, pretransplant MRD negativity was not associated with relapse (HR, 0.73; P = 0.420), treatment failure (HR, 0.64; P = 0.063), or overall mortality (HR, 0.69; P = 0.149) among patients with inv(16). In subgroup analysis, pretransplant MRD status significantly affected relapse and LFS only in patients with t(8;21) undergoing allogeneic HCT during CR2. In conclusion, our data demonstrate the different prognostic values of pretransplant MRD for CBF-AML, highlighting the need to develop effective therapeutic strategies for such MRD-positive patients.
Wilms’ tumor 1 (WT1) is a tumor-associated antigen and immunotherapy target in myelodysplastic syndrome (MDS). Further information is needed on the characteristics of WT1-specific CD8 + T cells to ...develop immunotherapeutic strategies for MDS. To clarify the frequency, distribution, and phenotype of WT1-specific CD8 + T cells, which occur innately in MDS patients, we analyzed paired peripheral blood (PB) and bone marrow (BM) samples from 39 patients with MDS or acute myeloid leukemia with myelodysplasia-related changes. The median frequency of WT1 tetramer-binding CD8 + T cells in the CD8 + T cell population was 0.11% in PB and 0.18% in BM. A further tetramer assay combined with mixed lymphocyte peptide culture (MLPC assay) was used to detect functional WT1-specific CD8 + T cells that could respond to the WT1 peptide. Functional WT1-specific CD8 + T cells were detected in BM in 61% of patients, which was significantly higher than in PB (23%,
p
= 0.001). The frequency of these cells estimated by the MLPC assay was tenfold higher in BM than in PB. The majority of WT1 tetramer-binding CD8 + T cells in BM had a unique phenotype with co-expression of CD39 and CXCR4. These findings will facilitate the development of novel immunotherapeutic strategies for MDS.
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