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Annals of Hematology 12/2012; · 2.62 Impact Factor
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ABSTRACT: Intracranial involvement of relapsed Hodgkin lymphoma (HL) is quite rare and its prognosis is very poor. We report a patient with relapsed HL with central nervous system (CNS) involvement after autologous stem cell transplantation successfully treated with allogeneic bone marrow transplantation with reduced intensity conditioning regimen. A standard therapy for relapsed CNS HL has not yet established. To the best of our knowledge, this is the first case report describing allogeneic stem cell transplantation for relapsed CNS HL in an elderly patient. Our results in this case suggest that allogeneic stem cell transplantation could be a useful therapeutic option in relapsed CNS HL patients, if their CNS lesions are controlled before stem cell transplantation.
[Rinshō ketsueki] The Japanese journal of clinical hematology 12/2012; 53(12):1991-6.
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Annals of Hematology 08/2012; · 2.62 Impact Factor
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British Journal of Haematology 07/2012; 158(6):798-800. · 4.94 Impact Factor
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Mayumi Yoshimi,
Susumu Goyama,
Masahito Kawazu,
Masahiro Nakagawa,
Motoshi Ichikawa, Yoichi Imai,
Keiki Kumano,
Takashi Asai,
James C Mulloy,
Andrew S Kraft,
Tsuyoshi Takahashi,
Naoki Shirafuji,
Mineo Kurokawa
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ABSTRACT: RUNX1 is essential for definitive hematopoiesis and T-cell differentiation. It has been shown that RUNX1 is phosphorylated at specific serine and threonine residues by several kinase families. However, it remains unclear whether RUNX1 phosphorylation is absolutely required for its biological functions. Here, we evaluated hematopoietic activities of RUNX1 mutants with serine (S)/threonine (T) to alanine (A), aspartic acid (D), or glutamic acid (E) mutations at phosphorylation sites using primary culture systems. Consistent with the results of knockin mice, RUNX1-2A, carrying two phospho-deficient mutations at S276 and S293, retained hematopoietic activity. RUNX1-4A, carrying four mutations at S276, S293, T300, and S303, showed impaired T-cell differentiation activity, but retained the ability to rescue the defective early hematopoiesis of Runx1-deficient cells. Notably, RUNX1-5A, carrying five mutations at S276, S293, T300, S303, and S462, completely lost its hematopoietic activity. In contrast, the phospho-mimic proteins RUNX1-4D/E and RUNX1-5D/E exhibited normal function. Our study identifies multiple phosphorylation sites that are indispensable for RUNX1 activity in hematopoiesis.
European Journal of Immunology 04/2012; 42(4):1044-50. · 5.10 Impact Factor
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ABSTRACT: We investigated the mechanisms of hematopoietic disorders caused by iron overload and chelation, in particular, the inhibition of erythroblast differentiation. Murine c-kit(+) progenitor cells or human CD34(+) peripheral blood hematopoietic progenitors were differentiated in vitro to the erythroid lineage with free iron and/or an iron chelator. Under iron overload, formation of erythroid burst-forming unit colonies and differentiation to mature erythroblasts were significantly suppressed; these effects were canceled by iron chelation with deferoxamine (DFO). Moreover, excessive iron burden promoted apoptosis in immature erythroblasts by elevating intracellular reactive oxygen species (ROS). Interestingly, both DFO and a potent anti-oxidant agent reduced intracellular ROS levels and suppressed apoptosis, thus restoring differentiation to mature erythroblasts. Accordingly, intracellular ROS may represent a new therapeutic target in the treatment of iron overload.
International journal of hematology 12/2011; 95(2):149-59. · 1.17 Impact Factor
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Masahiro Nakagawa,
Munetake Shimabe,
Naoko Watanabe-Okochi,
Shunya Arai,
Akihide Yoshimi,
Akihito Shinohara,
Nahoko Nishimoto,
Keisuke Kataoka,
Tomohiko Sato,
Keiki Kumano,
Yasuhito Nannya,
Motoshi Ichikawa, Yoichi Imai,
Mineo Kurokawa
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ABSTRACT: Functional deregulation of transcription factors has been found in many types of tumors. Transcription factor AML1/RUNX1 is one of the most frequent targets of chromosomal abnormalities in human leukemia and altered function of AML1 is closely associated with malignant transformation of hematopoietic cells. However, the molecular basis and therapeutic targets of AML1-related leukemia are still elusive. Here, we explored immediate target pathways of AML1 by in vitro synchronous inactivation in hematopoietic cells. We found that AML1 inhibits NF-κB signaling through interaction with IκB kinase complex in the cytoplasm. Remarkably, AML1 mutants found in myeloid tumors lack the ability to inhibit NF-κB signaling, and human cases with AML1-related leukemia exhibits distinctly activated NF-κB signaling. Furthermore, inhibition of NF-κB signaling in leukemic cells with mutated AML1 efficiently blocks their growth and development of leukemia. These findings reveal a novel role for AML1 as a cytoplasmic attenuator of NF-κB signaling and indicate that NF-κB signaling is one of the promising therapeutic targets of hematologic malignancies with AML1 abnormality.
Blood 12/2011; 118(25):6626-37. · 9.90 Impact Factor
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Keisuke Kataoka,
Tomohiko Sato,
Akihide Yoshimi,
Susumu Goyama,
Takako Tsuruta,
Hiroshi Kobayashi,
Munetake Shimabe,
Shunya Arai,
Masahiro Nakagawa, Yoichi Imai,
Keiki Kumano,
Katsuyoshi Kumagai,
Naoto Kubota,
Takashi Kadowaki,
Mineo Kurokawa
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ABSTRACT: Ecotropic viral integration site 1 (Evi1), a transcription factor of the SET/PR domain protein family, is essential for the maintenance of hematopoietic stem cells (HSCs) in mice and is overexpressed in several myeloid malignancies. Here, we generate reporter mice in which an internal ribosome entry site (IRES)-GFP cassette is knocked-in to the Evi1 locus. Using these mice, we find that Evi1 is predominantly expressed in long-term HSCs (LT-HSCs) in adult bone marrow, and in the hematopoietic stem/progenitor fraction in the aorta-gonad-mesonephros, placenta, and fetal liver of embryos. In both fetal and adult hematopoietic systems, Evi1 expression marks cells with long-term multilineage repopulating activity. When combined with conventional HSC surface markers, sorting according to Evi1 expression markedly enhances purification of cells with HSC activity. Evi1 heterozygosity leads to marked impairment of the self-renewal capacity of LT-HSCs, whereas overexpression of Evi1 suppresses differentiation and boosts self-renewal activity. Reintroduction of Evi1, but not Mds1-Evi1, rescues the HSC defects caused by Evi1 heterozygosity. Thus, in addition to documenting a specific relationship between Evi1 expression and HSC self-renewal activity, these findings highlight the utility of Evi1-IRES-GFP reporter mice for the identification and sorting of functional HSCs.
Journal of Experimental Medicine 11/2011; 208(12):2403-16. · 13.85 Impact Factor
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ABSTRACT: Dysfunction of AML1/Runx1, a transcription factor, plays a crucial role in the development of many types of leukemia. Additional events are often required for AML1 dysfunction to induce full-blown leukemia; however, a mechanistic basis of their cooperation is still elusive. Here, we investigated the effect of AML1 deficiency on the development of MLL-ENL leukemia in mice. Aml1 excised bone marrow cells lead to MLL-ENL leukemia with shorter duration than Aml1 intact cells in vivo. Although the number of MLL-ENL leukemia-initiating cells is not affected by loss of AML1, the proliferation of leukemic cells is enhanced in Aml1-excised MLL-ENL leukemic mice. We found that the enhanced proliferation is the result of repression of p19(ARF) that is directly regulated by AML1 in MLL-ENL leukemic cells. We also found that down-regulation of p19(ARF) induces the accelerated onset of MLL-ENL leukemia, suggesting that p19(ARF) is a major target of AML1 in MLL-ENL leukemia. These results provide a new insight into a role for AML1 in the progression of leukemia.
Blood 07/2011; 118(9):2541-50. · 9.90 Impact Factor
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Akihide Yoshimi,
Susumu Goyama,
Naoko Watanabe-Okochi,
Yumiko Yoshiki,
Yasuhito Nannya,
Eriko Nitta,
Shunya Arai,
Tomohiko Sato,
Munetake Shimabe,
Masahiro Nakagawa, Yoichi Imai,
Toshio Kitamura,
Mineo Kurokawa
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ABSTRACT: Evi1 (ecotropic viral integration site 1) is essential for proliferation of hematopoietic stem cells and implicated in the development of myeloid disorders. Particularly, high Evi1 expression defines one of the largest clusters in acute myeloid leukemia and is significantly associated with extremely poor prognosis. However, mechanistic basis of Evi1-mediated leukemogenesis has not been fully elucidated. Here, we show that Evi1 directly represses phosphatase and tensin homologue deleted on chromosome 10 (PTEN) transcription in the murine bone marrow, which leads to activation of AKT/mammalian target of rapamycin (mTOR) signaling. In a murine bone marrow transplantation model, Evi1 leukemia showed modestly increased sensitivity to an mTOR inhibitor rapamycin. Furthermore, we found that Evi1 binds to several polycomb group proteins and recruits polycomb repressive complexes for PTEN down-regulation, which shows a novel epigenetic mechanism of AKT/mTOR activation in leukemia. Expression analyses and ChIPassays with human samples indicate that our findings in mice models are recapitulated in human leukemic cells. Dependence of Evi1-expressing leukemic cells on AKT/mTOR signaling provides the first example of targeted therapeutic modalities that suppress the leukemogenic activity of Evi1. The PTEN/AKT/mTOR signaling pathway and the Evi1-polycomb interaction can be promising therapeutic targets for leukemia with activated Evi1.
Blood 02/2011; 117(13):3617-28. · 9.90 Impact Factor
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ABSTRACT: Optimal donor selection is one of the key factors to enhance the success rate of allogeneic hematopoietic stem cell transplantation (HSCT). The effect of sex mismatch, especially the effect of Y chromosome mismatch in graft-versus-host disease (GVHD) direction (female donors to male recipients: denoted as FtoM mismatch) on overall survival (OS) has been controversial and not examined out of the patient population in Western countries. We retrospectively analyzed 225 cases of allogeneic HSCT and showed that FtoM mismatch confers a highly significant impact on OS (P < 0.005) in Japanese population. We demonstrated that this effect depends on the disease risk; for standard risk cases, this effect was significantly associated with poor outcome (for OS, P = 0.021), while for high risk cases, it had no effect on the results (for OS, P = 0.26). We further showed that FtoM mismatch was associated with nonrelapse mortality (P = 0.019) and most of them were GVHD-related in standard risk cases. In conclusion, FtoM mismatch has a significant impact on transplant outcome, especially in standard risk cases.
Transplant International 02/2011; 24(5):469-76. · 2.92 Impact Factor
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ABSTRACT: Peripheral edema often occurs in patients with chronic myeloid leukemia (CML) treated with kinase inhibitors (TKIs). However, there are few reports indicating that the edema is caused by TKIs-induced hypothyroidism. We present the case of a 76-year-old man with chronic-phase CML who suffered from severe systemic edema after introduction of nilotinib. Laboratory tests revealed hypothyroidism; the patient was euthyroid prior to introduction of nilotinib. After further examination, we attributed this hypothyroidism to nilotinib. His edema regressed dramatically after thyroid hormone replacement therapy, with continued treatment with nilotinib. Laboratory examination of thyroid function also improved markedly. Although sunitinib, a multi-targeted TKI, is associated with a high incidence of hypothyroidism, TKIs targeting Bcr-Abl have rarely been reported to cause hypothyroidism. We report nilotinib-induced hypothyroidism, and suggest that hypothyroidism should be considered as a possible etiology when patients receivingTKIs suffer from edema.
International journal of hematology 02/2011; 93(3):400-2. · 1.17 Impact Factor
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ABSTRACT: B cell lymphoma, unclassifiable, with features intermediate between diffuse large B cell lymphoma and Burkitt lymphoma (BL) is a new entity in WHO classification 2008, and includes Burkitt-like transformation of follicular lymphoma (FL). However, the pathological significance of BCL-2/IgH translocation, which is characteristic in FL, in newly diagnosed cases of this disease is not well understood. We report a patient who developed B cell lymphoma with BL-like morphology on the shoulder, whose bone marrow was involved with FL-like cells. BL-like tumor cells harbored amplified c-MYC genes with BCL-2/IgH translocation, but FL-like cells solely had BCL-2/IgH translocation. The sequence analysis of the IgH gene revealed both of cells originated from the same clone, showing that the aggressive BL-like tumor originated from the FL-like clones simultaneously found in the bone marrow. This case suggests that the IgH/BCL-2 translocation found in newly diagnosed Burkitt-like lymphoma indicates a history of FL-like indolent lymphoma, even if such history is not documented.
International journal of hematology 01/2011; 93(1):112-7. · 1.17 Impact Factor
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ABSTRACT: The activating mutation of JAK2, V617F, has been found as a frequent mutation in myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF). This mutation is observed not only in MPNs, but also in chronic myelomonocytic leukemia, myelodysplastic syndrome and acute myeloid leukemia (AML). We report a case of myeloid sarcoma and myelofibrosis, followed by secondary AML, with detection of homozygous JAK2 V617F mutation. This report describes the first case of myeloid sarcoma with JAK2 V617F mutation and implication of its progression to AML.
Internal Medicine 01/2011; 50(21):2649-52. · 0.94 Impact Factor
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ABSTRACT: Ecotropic viral integration site-1 (Evi-1) is a nuclear transcription factor that plays an essential role in the regulation of hematopoietic stem cells. Aberrant expression of Evi-1 has been reported in up to 10% of patients with acute myeloid leukemia and is a diagnostic marker that predicts a poor outcome. Although chromosomal rearrangement involving the Evi-1 gene is one of the major causes of Evi-1 activation, overexpression of Evi-1 is detected in a subgroup of acute myeloid leukemia patients without any chromosomal abnormalities, which indicates the presence of other mechanisms for Evi-1 activation. In this study, we found that Evi-1 is frequently up-regulated in bone marrow cells transformed by the mixed-lineage leukemia (MLL) chimeric genes MLL-ENL or MLL-AF9. Analysis of the Evi-1 gene promoter region revealed that MLL-ENL activates transcription of Evi-1. MLL-ENL-mediated up-regulation of Evi-1 occurs exclusively in the undifferentiated hematopoietic population, in which Evi-1 particularly contributes to the propagation of MLL-ENL-immortalized cells. Furthermore, gene-expression analysis of human acute myeloid leukemia cases demonstrated the stem cell-like gene-expression signature of MLL-rearranged leukemia with high levels of Evi-1. Our findings indicate that Evi-1 is one of the targets of MLL oncoproteins and is selectively activated in hematopoietic stem cell-derived MLL leukemic cells.
Blood 12/2010; 117(23):6304-14. · 9.90 Impact Factor
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International journal of hematology 10/2010; 92(4):667-8. · 1.17 Impact Factor
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ABSTRACT: A 67-year-old man suffered from a left cervical lymph node swelling and tenderness. Biopsy of the cervical lymph node showed pleomorphic large cells containing large atypical nuclei. Immunohistochemical stains of these cells were positive for CD30, but negative for CD3 and CD20. After the biopsy, his left cervical skin was ulcerated. Biopsy of the left cervical skin was performed. Large pleomorphic cells with constricted nuclei and Reed-Sternberg-like cells existed in the dermis and epidermis. Immunohistochemical stains of the former cells were positive for CD30, CD45 and PAX5, but negative for CD3, CD10, CD20, CD15, Bcl-2, EBER ISH, EMA and ALK. He was diagnosed with diffuse large B cell lymphoma, anaplastic variant. He achieved complete remission with CHOP chemotherapy. CD30-positive DLBCL, anaplastic variant is a rare B cell lymphoma. Most of the patients presented with primary nodal disease, and skin involvement of lymphoma is very rare. This is the report of a rare case of CD30-positive DLBCL, anaplastic variant, with both nodal and skin lesions.
International journal of hematology 10/2010; 92(3):550-2. · 1.17 Impact Factor
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ABSTRACT: Waldenström macroglobulinemia (WM) is characterized by serum IgM monoclonal gammopathy, and only occasionally complicated by immune thrombocytopenia. Rarely, coexistence of non-IgM gammopathy in WM has been reported. Herein, we describe an 81-year-old case of WM with rapidly progressive immune thrombocytopenia accompanied by concurrent IgG gammopathy and elevation of platelet-associated IgG (PA-IgG). Immunostaining of the bone marrow specimen displayed not only IgM positive but also IgG positive plasmacytoid cells. Although dexamethasone therapy had no effect on thrombocytopenia, a modified RCD regimen (rituximab 375 mg/m(2) i.v. day 1, cyclophosphamide 375 mg/m(2) i.v. day 2 and dexamethasone 12 mg/body orally days 1-7) successfully normalized PA-IgG as well as IgG and IgM paraproteinemia and significantly increased platelet count. The current case suggests that the IgG gammopathy associated with WM is likely to be an etiology of immune thrombocytopenia and that tumor reduction, rather than immunosuppression, leads to an improvement of concurrent thrombocytopenia.
International journal of hematology 09/2010; 92(2):360-3. · 1.17 Impact Factor
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ABSTRACT: Post-transplant lymphoproliferative disorder (PTLD) is a serious complication of solid organ transplant. Although living donor liver transplant (LDLT) has been increasingly performed, PTLD after LDLT has not been well investigated. We aimed to determine the clinical characteristics of PTLD after LDLT. We investigated 323 consecutive patients undergoing adult-to-adult LDLT and identified three patients who developed biopsy-proven PTLD. All of them were seropositive for Epstein-Barr virus (EBV) and had hepatitis C virus-related cirrhosis at transplant. All three patients developed late-onset and monomorphic PTLD, including one diffuse large B-cell lymphoma and two Burkitt lymphomas with c-myc rearrangement. Two of them were EBV negative. The initial therapy included chemotherapy, rituximab, and immunosuppression withdrawal. One patient died of sepsis during treatment and two patients achieved complete responses. We showed a relatively low incidence and distinct clinicopathological features of PTLD after adult-to-adult LDLT, which might reflect the unique nature of LDLT.
Leukemia & lymphoma 08/2010; 51(8):1494-501. · 2.40 Impact Factor
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ABSTRACT: Familial platelet disorder (FPD) is a rare autosomal dominant disorder which causes moderate thrombocytopenia with or without impaired platelet function. Patients have a propensity to develop acute myeloid leukemia (AML), and various types of second hits have been postulated in the evolution to AML. However, only a few cases of acute lymphoblastic leukemia (ALL) have been reported thus far. Here, we report a family of FPD with a germ-line hemi-allelic mutation R174X in the RUNX1 gene. The proband of the family developed AML and her son had ALL of the T cell lineage. The balanced translocation t(1;7)(p34.1;q22) was detected in the lymphoblasts from the patient with ALL. This translocation was not seen in any other affected members of the family or in the bone marrow sample of this patient in complete remission. Taken together, t(1;7)(p34.1;q22) is thought to be one of the somatic second hits that predisposes FPD to acute leukemia with T cell phenotype.
International journal of hematology 07/2010; 92(1):194-7. · 1.17 Impact Factor
