Retinoic acid related orphan receptor gamma-t (RORgammat) is known to be a master regulator of Th17-cell development. In this study, we generated RORgammat-overexpressing transgenic (RORgammat Tg) ...mice in which transgene expression was driven by the CD2 promoter, and found that these mice developed polyclonal plasmacytosis and autoantibody production. RORgammat Tg mice were generated on a C57BL/6 background, and also were intercrossed with BALB/c mice. BALB/c F1 (BALB/F1) RORgammat Tg mice developed massive polyclonal plasma-cytosis, and had shorter life spans. Splenomegaly and infiltration of plasma cells into the lung were observed. Hyperglobulinemia, anti-double-stranded DNA antibodies, anti-erythrocyte antibodies, and anti-platelet antibodies were detected in BALB/F1 RORgammat Tg mice. In the present study, polyclonal plasmacytosis in BALB/F1 RORgammat Tg mice appeared to be due to the induction of excessive IL-6 production by IL-17. We detected increased numbers of CD11b+ cells that produced IL-6. We also generatedIL-6-deficient RORgammat Tg BALB/F1 background mice, which displayed high levels of serum IL-17, but did not develop severe hyperglobulinemia. Excessive IL-6 production by several cell types, including macrophages, in BALB/F1 RORgammat Tg mice, might effect the development of plasma-cytosis. These results suggest that RORgammat plays important roles in the development of plasmacytosis and autoantibody production. PUBLICATION ABSTRACT
Abstract 3646
Poster Board III-582
c-Maf is one of the large Maf (musculoaponeurotic fibrosarcoma) transcription factors that belong to the AP1 super family of basic leucine zipper proteins. c-Maf ...has been shown to be important for the regulation of IL-4 and IL-21 gene expression in T-helper-2 cells and the formation of the lens structure. A recent report has demonstrated that the augmentation of c-Maf gene expression was observed in myeloma cell lines and bone marrow samples of multiple myeloma patients. It suggests that c-Maf plays important role in multiple myeloma pathogenesis. However, the physiological roles of c-Maf in normal hematopoiesis are largely unknown and have never been analyzed in vivo setting. In this study, we investigated that c-Maf is indispensable for hematopoesis via analyzing c-Maf deficient (c-Maf−/−) mice. In the C57BL/6J background, c-Maf−/− mice were embryonic lethal and it died between embryonic day (E) 15 and E18. c-Maf−/− embryo looked pale and had evidence of anemia. In c-Maf−/− peripheral blood at E14.5, the number of enucleated erythrocytes was decreased compared that in wild-type (WT) littermates. Flow cytometric analysis of fetal liver cells indicated that mature red blood cells were reduced in c-Maf−/− embryos. In addition, Annexin-V positive apoptotic cells were increased in c-Maf−/− fetal liver. Interestingly, there was no significant difference between WT and c-Maf−/− fetal liver cells in erythroid colony counts on the colony-forming unit assay. These results indicated that c-Maf−/− erythroid cells can develop to mature cells, and the impaired definitive erythropoiesis in the c-Maf−/− mice is due to a non-cell-autonomous effect. Immunohistochemical staining of WT fetal liver using anti-c-Maf antibody showed that c-Maf was highly expressed in macrophage but not in erythroid cells. For this reason, we hypothesized that c-Maf−/− macrophage was responsible for anemia of c-Maf−/− embryo. The erythropoietic microenvironment in fetal liver mainly consists of clusters of erythroblastic islands that made up of central macrophage and surrounding erythroblasts. The compromise of erythroblasitc islands through defect of macrophage causes anemia and embryonic lethality. To verify whether c-Maf−/− macrophage cause fail to form erythroblasitic island, we isolated the erythroblasitc island from WT and c-Maf−/− fetal liver. As a result, the number of erythroblast surrounding the macrophage in erythroblastic island was significantly reduced in c-Maf−/− mice. Moreover, in vitro reconstitution experiments showed that c-Maf−/− erythroblasts were able to form erythroblastic island with WT macrophages, while c-Maf−/− macrophages and WT erythroblasts could not form erythroblastic island. These results strongly suggest that the cause of anemia in c-Maf−/− mice is due to abnormal function of macrophages in forming erythroblastic island. Finally, to clarify the molecular mechanism in formation of erythroblastic island, we found the target gene of c-Maf in fetal liver macrophages. The DNA microarray and real time RT-PCR analyses showed that the decreased expression of vascular adhesion molecule 1 (VCAM-1), known as an adhesion molecule expressed on macrophage of erythroblastic island, was observed in c-Maf−/− fetal liver macrophage. We conclude that c-Maf is indispensable for definitive hematopoiesis and erythroblastic island formation through crucial roll in fetal liver macrophages.
No relevant conflicts of interest to declare.
A 53-year-old man diagnosed with adult T-cell lymphoma (ATL) was treated with mLSG15 chemotherapy and achieved a first complete remission. Subsequently, a liver tumor emerged that was pathologically ...diagnosed as ATL (first relapse). A second remission was achieved after local irradiation and four cycles of mogamulizumab treatment. The patient received peripheral blood stem cell transplantation (HSCT) from a one haplotype HLA-mismatched daughter after total body irradiation and the administration of fludarabine as a myeloablative conditioning regimen, followed by post-transplant cyclophosphamide. While subsequent acute graft-versus-host disease (GVHD) was never more than Grade I, severe chronic GVHD (cGVHD) developed in the oral cavity and skin that was resistant to escalated doses of cyclosporine and prednisolone. The patient subsequently had a second relapse of ATL as a subcutaneous mass and eventually died of disease progression. Mogamulizumab is a humanized monoclonal IgG that targets CC chemokine receptor 4 (CCR4) and is a key treatment option for relapsed ATL. It reportedly increases the risk of acute GVHD after HSCT due to the depletion of CCR4-positive regulatory T-cells; however, information on its impact on cGVHD is unavailable. Here, we discuss the potential risks and benefits of mogamulizumab, particularly in a haploidentical donor setting during a HSCT for ATL.
Retinoic acid related orphan receptor gamma‐t (
ROR
γt) is known to be a master regulator of
T
h17‐cell development. In this study, we generated
ROR
γt‐overexpressing transgenic (
ROR
γt
T
g) mice in ...which transgene expression was driven by the
CD
2 promoter, and found that these mice developed polyclonal plasmacytosis and autoantibody production.
ROR
γt
T
g mice were generated on a
C
57
BL
/6 background, and also were intercrossed with
B
ALB/c mice.
B
ALB/c
F
1 (
B
ALB/
F
1)
ROR
γt
T
g mice developed massive polyclonal plasma‐cytosis, and had shorter life spans. Splenomegaly and infiltration of plasma cells into the lung were observed. Hyperglobulinemia, anti‐double‐stranded
DNA
antibodies, anti‐erythrocyte antibodies, and anti‐platelet antibodies were detected in
B
ALB/
F
1
ROR
γt
T
g mice. In the present study, polyclonal plasmacytosis in
B
ALB/
F
1
ROR
γt
T
g mice appeared to be due to the induction of excessive
IL
‐6 production by
IL
‐17. We detected increased numbers of
CD
11b
+
cells that produced
IL
‐6. We also generated
IL
‐6‐deficient
ROR
γt
T
g
B
ALB/
F
1 background mice, which displayed high levels of serum
IL
‐17, but did not develop severe hyperglobulinemia. Excessive
IL
‐6 production by several cell types, including macrophages, in
B
ALB/
F
1
ROR
γt
T
g mice, might effect the development of plasma‐cytosis. These results suggest that
ROR
γt plays important roles in the development of plasmacytosis and autoantibody production.
Acute promyelocytic leukemia (APL) is characterized by chromosomal rearrangements of 17q21, leading to fusion of the gene‐encoding retinoic acid receptor alpha (RARA) with a number of alternative ...partner genes. Signal transducer and activator of transcription 5 beta (STAT5B) is one of the alternative partners. We report a rare case of APL with STAT5B–RARA fusion transcript and the normal chromosome 17 on G‐banding. Administration of all trans‐retinoic acid improved disseminated intravascular coagulation without decrease of the leukemia cells in his peripheral blood and bone marrow. The molecular mechanism of fusion between STAT5B and RARA by chromosomal rearrangement is discussed based on the data from genome database. Clinical characteristics of APL with STAT5B–RARA are also discussed.
This report describes a 30-year-old man with a testicular germ cell tumor, which later developed into acute myeloid leukemia (AML) with a common chromosomal abnormality. Testicular germ cell tumors ...had developed at the age of 26. He was successfully treated with surgery followed by chemotherapy.Four years after the onset of the germ cell tumor, he developed pancytopenia with elevated serum LDH. More than 95% of the bone marrow was occupied by blastic cells. These cells were CD13+, CD34+ but CD45- and MPO-. Amplification of the short arm of chromosome 12 was recognized by fluorescence in situ hybridization using the blastic cells in the bone marrow and the previous testicular tumor specimen. Because testicular germ cell tumor recurrence and other malignant tumors could be ruled out pathologically, he was diagnosed as having AML.Allogeneic stem cell transplantation from a HLA-matched sibling donor was performed after chemotherapy. As of 19 months after the transplantation, recurrence of neither AML nor testicular tumors has been observed. Because the same genetic abnormality was observed in the testicular germ cell tumor and AML in this case, the possibility of AML having a common origin with the testicular germ cell tumor is indicated.
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