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1.
Int J Hematol ; 113(5): 723-734, 2021 May.
Article in English | MEDLINE | ID: mdl-33502734

ABSTRACT

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.


Subject(s)
Bone Marrow/immunology , CD8 Antigens/analysis , Myelodysplastic Syndromes/immunology , T-Lymphocytes, Cytotoxic/immunology , WT1 Proteins/analysis , Adult , Aged , Aged, 80 and over , CD8 Antigens/immunology , Humans , Middle Aged , WT1 Proteins/immunology
2.
Transfusion ; 59(8): 2519-2522, 2019 08.
Article in English | MEDLINE | ID: mdl-30990901

ABSTRACT

BACKGROUND: The Rh complex contributes to cell membrane structural integrity of erythrocytes. Rhnull syndrome is characterized by the absence of the Rh antigen on the erythrocyte membrane, resulting in chronic hemolytic anemia. We recently came across 3 Rhnull phenotype probands within two families with the same novel RHAG mutation in the Japanese population. MATERIALS AND METHODS: Detailed Rh phenotyping by hemagglutination was performed using monoclonal and polyclonal anti-D, -C, -c, -E, and -e; monoclonal and polyclonal anti-Rh17 antibodies; and polyclonal anti-Rh29 antibodies. RHAG mRNA transcripts were analyzed by reverse transcription-polymerase chain reaction, and the mutation was verified by genomic sequencing. RESULTS: The genomic region spanning exon 6 contained a G > A transition in the invariant GT motif of the 5' donor splice-site of Intron 6 (c.945+1G>A). The Rhnull phenotype was caused by an autosomal recessive mutation in Probands 1 and 2, determined by family history. Regarding clinical features, the degree of hemolysis varied slightly between these individuals, with Proband 3 displaying acute hemolytic anemia with an infection. While no standard therapy has been established, the condition of the patient in this study improved with conservative treatment, including hydration and antibiotics. CONCLUSION: The mechanisms of hemolysis due to the Rhnull phenotype can vary, but our findings indicate that acute hemolytic crisis caused by the Rhnull syndrome could be associated with infection.


Subject(s)
Blood Proteins/genetics , Membrane Glycoproteins/genetics , Mutation , Asian People , Blood Grouping and Crossmatching , DNA Mutational Analysis , Hemolysis/genetics , Humans , Japan , Male , Membrane Glycoproteins/blood , Middle Aged
3.
Int J Hematol ; 107(3): 337-344, 2018 Mar.
Article in English | MEDLINE | ID: mdl-29043551

ABSTRACT

Membrane-associated guanylate kinase with inverted orientation protein 1 (MAGI-1) is a cytoplasmic scaffold protein that interacts with various signaling molecules; it negatively controls the cell growth of various types of cells and positively controls cell-cell interaction. In T cells, MAGI-1 has been shown to inhibit Akt activity through its interaction with PTEN and MEK1. In this study we found that MAGI-1 expression is decreased in multiple (9 out of 15) human T-cell leukemia cell lines, including adult T-cell leukemia (ATL), T-cell acute lymphoblastic leukemia and chronic T-cell lymphocytic leukemia. The overexpression of MAGI-1 protein in a MAGI-1-low ATL cell line reduced cellular growth. While the overexpression of MAGI-1 protein in a MAGI-1-low ATL cell line reduced the Akt and MEK activities, the knockdown of MAGI-1 in a MAGI-1-high ATL cell line augmented the Akt and MEK activities. Collectively, the findings of the present study suggest that the decreased expression of MAGI-1 in human T cells contributes to the development of several types of T-cell leukemia, partly through the stimulation of the Akt and MEK pathways.


Subject(s)
Cell Adhesion Molecules, Neuronal/genetics , Cell Adhesion Molecules, Neuronal/metabolism , Gene Expression , Leukemia, T-Cell/genetics , Leukemia, T-Cell/pathology , Leukemia-Lymphoma, Adult T-Cell/genetics , Leukemia-Lymphoma, Adult T-Cell/pathology , Adaptor Proteins, Signal Transducing , Cell Adhesion Molecules , Cell Line, Tumor , Cell Proliferation/genetics , Guanylate Kinases , Humans , MAP Kinase Kinase 1 , Oncogene Protein v-akt , Signal Transduction
4.
Rinsho Ketsueki ; 58(12): 2402-2405, 2017.
Article in Japanese | MEDLINE | ID: mdl-29332874

ABSTRACT

A 75-year-old woman suffered a cat bite 10 months after myelodysplastic syndrome (MDS) diagnosis. She visited our hospital because the internal bleeding of the wound did not improve. Although the wound was treated, the bleeding did not stop. She was hospitalized for emergency medical treatment because the bleeding volume exceeded 200 ml. Although her platelet count was normal, the platelet function test showed a decrease in collagen and arachidonic acid aggregation. After platelet transfusion, her bleeding stopped. Patients with MDS may potentially have platelet dysfunction. In the case of bleeding without thrombocytopenia, a platelet function test should be performed and treatment intervention, such as platelet transfusion, should be considered.


Subject(s)
Blood Platelet Disorders/etiology , Hemorrhage/therapy , Myelodysplastic Syndromes/complications , Aged , Blood Transfusion , Female , Hemorrhage/etiology , Humans , Platelet Aggregation , Treatment Outcome
5.
Leuk Res ; 39(6): 667-71, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25890432

ABSTRACT

We focused on the level of reduction of Wilms' tumor gene 1 (WT1) mRNA in bone marrow as minimal residual disease during chemotherapies in adult acute myeloid leukemia (AML) patients. Forty-eight patients were enrolled in this study. Log levels of reduction of WT1 mRNA transcript after induction therapy compared with those at diagnosis were associated with disease-free survival (DFS) (P=0.0066) and overall survival (OS) (P=0.0074) in patients who achieved complete remission. Also log levels of reduction of WT1 mRNA transcript after final consolidation therapy compared with those at diagnosis were associated with DFS (P=0.015) and OS (P=0.012). By multivariate analysis, log levels of reduction of WT1 mRNA transcript after induction therapy and after final consolidation therapy compared with those at diagnosis were extracted as risk factors for outcome. Our results suggest that early and deep reduction of tumor burden may be important for the outcome of AML patients. In addition, it may be useful for the decision to proceed with allogeneic SCT as post-remission therapy.


Subject(s)
Bone Marrow , Consolidation Chemotherapy , Induction Chemotherapy , RNA, Messenger/metabolism , RNA, Neoplasm/metabolism , WT1 Proteins/metabolism , Adolescent , Adult , Aged , Bone Marrow/metabolism , Bone Marrow/pathology , Disease-Free Survival , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/pathology , Middle Aged , Risk Factors , Survival Rate
6.
Intern Med ; 53(18): 2115-9, 2014.
Article in English | MEDLINE | ID: mdl-25224199

ABSTRACT

We herein report the case of a 22-year-old woman with severe aplastic anemia who underwent allogeneic hematopoietic stem cell transplantation (HSCT). After HSCT, the Epstein-Barr virus (EBV)-DNA load in the peripheral blood gradually increased, and the patient presented with a fever and lymphadenopathy on day 56 post-HSCT. Although we administered rituximab, her clinical condition worsened. After rituximab treatment, CD8 T-cells emerged and became dominant in the peripheral blood, some of which were positive on an EBV-specific tetramer analysis. However, an open biopsy of the lymphadenopathy lesions revealed the CD8 T-cells to be infected with EBV, exhibiting proliferation with oligoclonality. The patient ultimately died of multiple organ failure on day 99 post-HSCT.


Subject(s)
Antibodies, Monoclonal, Murine-Derived/adverse effects , CD8-Positive T-Lymphocytes/immunology , DNA, Viral/analysis , Epstein-Barr Virus Infections/virology , Hematopoietic Stem Cell Transplantation , Herpesvirus 4, Human/genetics , Lymphoproliferative Disorders/etiology , Anemia/therapy , Antibodies, Monoclonal, Murine-Derived/therapeutic use , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Epstein-Barr Virus Infections/complications , Female , Herpesvirus 4, Human/physiology , Humans , Lymphoproliferative Disorders/diagnosis , Lymphoproliferative Disorders/immunology , Rituximab , Virus Replication , Young Adult
7.
Intern Med ; 52(11): 1239-42, 2013.
Article in English | MEDLINE | ID: mdl-23728563

ABSTRACT

A 51-year-old man was admitted due to a severe bleeding tendency. After he was diagnosed with immune thrombocytopenia (ITP), several therapies, including steroids, steroid pulse, vincristine and rituximab, were administered; however, the patient's bleeding symptoms were not sufficiently controllable with these treatments. Subsequently, a diffuse alveolar hemorrhage was observed. Treatment with a thrombopoietin receptor agonist, romiplostim, was initiated to prevent lethal hemorrhaging, although the efficacy of thrombopoietic receptor agonists in such emergency situations has not been elucidated. The initiation of romiplostim achieved prompt remission in platelets. This case suggests that combination therapy with romiplostim, rituximab and vincristine is effective in cases of newly diagnosed severe therapy-resistant ITP.


Subject(s)
Antibodies, Monoclonal, Murine-Derived/administration & dosage , Hemorrhage/drug therapy , Pulmonary Alveoli/pathology , Receptors, Fc/administration & dosage , Recombinant Fusion Proteins/administration & dosage , Thrombocytopenia/drug therapy , Thrombopoietin/administration & dosage , Vincristine/administration & dosage , Drug Therapy, Combination , Hemorrhage/complications , Hemorrhage/diagnosis , Humans , Male , Middle Aged , Pulmonary Alveoli/drug effects , Rituximab , Severity of Illness Index , Thrombocytopenia/complications , Thrombocytopenia/diagnosis , Treatment Outcome
8.
Intern Med ; 50(5): 481-5, 2011.
Article in English | MEDLINE | ID: mdl-21372464

ABSTRACT

We describe a 60-year-old Japanese patient with chronic myeloid leukemia (CML) who developed myelodysplastic syndrome (MDS) with Ph negative monosomy 7 chromosome following transient bone marrow dysplasia during imatinib treatment. Most cases that developed chromosomal abnormality in Ph negative cells during imatinib therapy were reported to have less clinical implications, while rare cases developed MDS/AML. The present case suggested that metaphase karyotype analysis and bone marrow examination should be performed for the long term follow-up under imatinib treatment in cases showing cytopenia. The results also suggested that monosomy 7 in Ph negative cells may be an indicator of a poor prognosis.


Subject(s)
Antineoplastic Agents/adverse effects , Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative/drug therapy , Myelodysplastic Syndromes/etiology , Myelodysplastic Syndromes/genetics , Piperazines/adverse effects , Pyrimidines/adverse effects , Benzamides , Bone Marrow/pathology , Chromosome Deletion , Chromosomes, Human, Pair 7 , Humans , Imatinib Mesylate , In Situ Hybridization, Fluorescence , Karyotyping , Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative/genetics , Male , Middle Aged , Myelodysplastic Syndromes/pathology
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