論文 - 片岡　圭亮

Ecotropic viral integration site 1, stem cell self-renewal and leukemogenesis

Kataoka, K. and Kurokawa, M.

Cancer Sci 103 （ 8 ） 1371 - 7 2012年08月

ISSN  1349-7006

　概要を見る

It has become evident that acute myeloid leukemia (AML) is organized as a cellular hierarchy initiated and maintained by a subset of self-renewing leukemia stem cells. Recent gene expression profile analysis of human leukemia stem cells and hematopoietic stem cell (HSC) populations identified a key transcriptional program shared by leukemia stem cells and HSC, which is associated with adverse outcomes in AML patients. One molecule that has been established as a pivotal regulator in fine-tuning of stem cell properties as well as a potent oncogenic determinant is ecotropic viral integration site 1 (EVI1). EVI1 is a transcription factor that has stem cell-specific expression pattern and is essential for the regulation of HSC self-renewal. This gene is notorious for its involvement in AML, as its activation confers extremely poor prognosis in patients with AML. Molecular analysis has identified a variety of gene products that are involved in HSC regulation as downstream targets or interacting proteins of EVI1. Thus, exploration of the molecular pathogenesis underlying EVI1-related leukemogenesis provides insight into how shared stemness transcriptional programs contribute to leukemia progression and therapeutic resistance in AML. Here, we review the current knowledge regarding the role of EVI1 in HSC self-renewal and leukemogenesis and highlight the relationship between stem cell self-renewal properties and adverse outcome in myeloid malignancies.

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AML1/RUNX1 functions as a cytoplasmic attenuator of NF-kappaB signaling in the repression of myeloid tumors

Nakagawa, M., Shimabe, M., Watanabe-Okochi, N., Arai, S., Yoshimi, A., Shinohara, A., Nishimoto, N., Kataoka, K., Sato, T., Kumano, K., Nannya, Y., Ichikawa, M., Imai, Y. and Kurokawa, M.

Blood 118 （ 25 ） 6626 - 37 2011年12月

ISSN  1528-0020

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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-kappaB signaling through interaction with IkappaB kinase complex in the cytoplasm. Remarkably, AML1 mutants found in myeloid tumors lack the ability to inhibit NF-kappaB signaling, and human cases with AML1-related leukemia exhibits distinctly activated NF-kappaB signaling. Furthermore, inhibition of NF-kappaB 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-kappaB signaling and indicate that NF-kappaB signaling is one of the promising therapeutic targets of hematologic malignancies with AML1 abnormality.

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Evi1 is essential for hematopoietic stem cell self-renewal, and its expression marks hematopoietic cells with long-term multilineage repopulating activity

Kataoka, K., Sato, T., Yoshimi, A., Goyama, S., Tsuruta, T., Kobayashi, H., Shimabe, M., Arai, S., Nakagawa, M., Imai, Y., Kumano, K., Kumagai, K., Kubota, N., Kadowaki, T. and Kurokawa, M.

J Exp Med 208 （ 12 ） 2403 - 16 2011年11月

ISSN  1540-9538

　概要を見る

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.

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The negative impact of female donor/male recipient combination in allogeneic hematopoietic stem cell transplantation depends on disease risk

Nannya, Y., Kataoka, K., Hangaishi, A., Imai, Y., Takahashi, T. and Kurokawa, M.

Transpl Int 24 （ 5 ） 469 - 76 2011年05月

ISSN  1432-2277

　概要を見る

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.

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Pretransplant predictors and posttransplant sequels of acute kidney injury after allogeneic stem cell transplantation

Kagoya, Y., Kataoka, K., Nannya, Y. and Kurokawa, M.

Biol Blood Marrow Transplant 17 （ 3 ） 394 - 400 2011年03月

ISSN  1523-6536

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Acute kidney injury (AKI) is a common complication after allogeneic stem cell transplantation (SCT). Although various risk factors for AKI have been reported, the influence of pretransplant comorbidity on the incidence of AKI has not been well investigated. We performed a retrospective analysis of 207 consecutive patients undergoing myeloablative or nonmyeloablative SCT between 2001 and 2009, using the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) as a representative of pretransplant comorbidities. According to Risk, Injury, Failure, Loss, and End-stage kidney disease (RIFLE) criteria, 158 patients (76.3%) developed AKI, and 92 patients (44.4%) developed severe AKI (RIFLE class I or class F) within 100 days after SCT. The cumulative incidence of severe AKI within 100 days in patients with an HCT-CI score 0, 1-2, and >/=3 was 21.3%, 48.8%, and 73.9%, respectively. In multivariate analysis, the HCT-CI was independently associated with severe AKI (HCT-CI 1-2: adjusted hazard ratio [HR] 2.42, P < .01; HCT-CI >/=3: adjusted HR 4.69, P < .01). In a landmark analysis, patients with severe AKI had a lower 3-year overall survival (OS) (39.3% versus 61.4%, P < .01), and a higher 3-year nonrelapse mortality (NRM) (40.8% versus 5.6%, P < .01) than those without AKI. Multivariate analysis showed that severe AKI was a significant risk factor for worse OS (HR: 2.10, P = .01) and NRM (HR: 6.15, P < .01). Thus, it is important to assess the HCT-CI to predict the incidence of AKI, which is a strong indicator of worse prognosis after SCT.

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Outcome and treatment of late-onset noninfectious pulmonary complications after allogeneic haematopoietic SCT

Ueda, K., Watadani, T., Maeda, E., Ota, S., Kataoka, K., Seo, S., Kumano, K., Hangaishi, A., Takahashi, T., Imai, Y., Ohtomo, K., Fukayama, M., Nannya, Y. and Kurokawa, M.

Bone Marrow Transplant 45 （ 12 ） 1719 - 27 2010年12月

ISSN  1476-5365

　概要を見る

Late-onset noninfectious pulmonary complications (LONIPCs) are life threatening for allogeneic hematopoietic SCT (allo-HSCT) recipients. However, the impact of LONIPCs on survival has not been properly evaluated and little is known about treatment efficacy. We retrospectively investigated 290 allo-HSCT recipients in our institute and reviewed the clinical aspects of 44 patients who had been diagnosed with LONIPCs. LONIPCs were significantly associated with higher rates of chronic GVHD (P<0001) and nonrelapse mortality (P=0.013), and lower rates of relapse (P=0.009). As a result of these effects, OS was significantly worse in those with LONIPCs (P=0.003). This result differs from a previous report. We then assessed short-term treatment response and final outcome. These results were defined by radiological findings, subjective symptoms, oxygen requirement and survival. Use of inhaled and systemic steroids did not affect either short-term response or final outcomes. However, administration of systemic corticosteroids earlier than at 21 days (median interval of time from onset of symptoms to systemic corticosteroids administration) was associated with a better outcome (P=0.054 for short-term response, and 0.016 for final outcome). Our study indicates that LONIPCs reduce OS, and early intervention with systemic corticosteroids may be effective.

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Plasma brain natriuretic peptide is associated with hepatic veno-occlusive disease and early mortality after allogeneic hematopoietic stem cell transplantation

Kataoka, K., Nannya, Y., Iwata, H., Seo, S., Kumano, K., Takahashi, T., Nagai, R. and Kurokawa, M.

Bone Marrow Transplant 45 （ 11 ） 1631 - 7 2010年11月

ISSN  1476-5365

　概要を見る

Fluid retention is characteristic of veno-occlusive disease (VOD). We hypothesized that plasma brain natriuretic peptide (BNP), a neurohormone secreted in response to volume expansion, may be associated with VOD after hematopoietic stem cell transplantation (HSCT). BNP was measured before and weekly after HSCT in 46 recipients. Sixteen patients developed VOD. BNP concentrations were similar before and on day 0 in patients with and without VOD, but were significantly higher on day 7 and later in those with VOD. Patients with VOD had significantly higher peak BNP concentrations before engraftment than those without VOD (median, 634.4 versus 80.9 pg ml(-)(1); P=0.01). Multivariate analysis showed that VOD was independently associated with BNP elevation (odds ratio, 50.1; 95% CI: 5.2-478.4; P<0.01). Landmark analysis at day 7 showed that patients with peak BNP concentration of >/= 180 pg ml(-)(1) had significantly worse 100-day survival than patients with peak BNP <180 pg ml(-)(1) (54 versus 91%; P<0.01). In multivariate analysis, BNP elevation before day 7 significantly predicted 100-day survival (hazard ratio 5.3; 95% CI: 1.1-24.3; P=0.03). These findings suggest that plasma BNP may serve as a diagnostic and prognostic marker of VOD.

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Post-transplant lymphoproliferative disorder after adult-to-adult living donor liver transplant: case series and review of literature

Kataoka, K., Seo, S., Sugawara, Y., Ota, S., Imai, Y., Takahashi, T., Fukayama, M., Kokudo, N. and Kurokawa, M.

Leuk Lymphoma 51 （ 8 ） 1494 - 501 2010年08月

ISSN  1029-2403

　概要を見る

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.

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Positron emission tomography in the diagnosis and therapeutic monitoring of post-transplant lymphoproliferative disorder after cord blood transplantation

Kataoka, K., Seo, S., Ota, S., Takahashi, T. and Kurokawa, M.

Bone Marrow Transplant 45 （ 3 ） 610 - 2 2010年03月

ISSN  1476-5365

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Differential prognostic impact of pretransplant comorbidity on transplant outcomes by disease status and time from transplant: a single Japanese transplant centre study

Kataoka, K., Nannya, Y., Ueda, K., Kumano, K., Takahashi, T. and Kurokawa, M.

Bone Marrow Transplant 45 （ 3 ） 513 - 20 2010年03月

ISSN  1476-5365

　概要を見る

This retrospective study examined the differences in the prognostic impact of the haematopoietic cell transplantation-specific comorbidity index (HCT-CI) on transplant outcomes by disease status and time from transplant in allogeneic haematopoietic stem cell transplantation (HSCT) recipients at a Japanese transplant centre. Of 187 patients, nonrelapse mortality (NRM) at 3 years was 9.6, 21.2 and 27.8% in the low-risk (score 0), intermediate-risk (score 1-2) and high-risk (score > or =3) HCT-CI groups, respectively (P=0.03). The corresponding overall survival (OS) at 3 years was 70.1, 60.5 and 38.9%, respectively (P<0.01). In multivariate analyses, high-risk HCT-CI significantly predicted higher NRM (relative risk, (RR) 2.44 (95% confidence interval, (CI) 1.02-5.85); P=0.04) and worse OS (RR 2.02 (95% CI 1.15-3.54); P=0.01). In the subgroup analysis according to disease status, the HCT-CI was associated with OS (P<0.01) and NRM (P=0.07) in patients with low-risk diseases, but not in those with high-risk diseases. Within patients who survived without relapse >1 year after HSCT, the HCT-CI did not predict OS (P=0.59) or NRM (P=0.31). These findings can be useful to determine the role of pretransplant comorbidity in allogeneic HSCT.

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Fulminant myocarditis after allogeneic bone marrow transplantation: successful cytomegalovirus therapy and mechanical circulatory support for bridge to recovery

Kataoka, K., Takahashi, T., Iwata, H., Hangaishi, A., Kumano, K. and Kurokawa, M.

Biol Blood Marrow Transplant 16 （ 1 ） 129 - 30 2010年01月

ISSN  1523-6536

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Interstitial pneumonia associated with progression of myelodysplastic syndrome

Kataoka, K., Ichikawa, M., Hangaishi, A., Takahashi, T., Imai, Y. and Kurokawa, M.

Int J Hematol 89 （ 5 ） 718 - 9 2009年06月

ISSN  1865-3774

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Influence of pretransplantation serum ferritin on nonrelapse mortality after myeloablative and nonmyeloablative allogeneic hematopoietic stem cell transplantation

Kataoka, K., Nannya, Y., Hangaishi, A., Imai, Y., Chiba, S., Takahashi, T. and Kurokawa, M.

Biol Blood Marrow Transplant 15 （ 2 ） 195 - 204 2009年02月

ISSN  1523-6536

　概要を見る

Iron overload might be an important contributor to nonrelapse mortality (NRM) in hematopoietic stem cell transplantation (HSCT). We studied 264 patients undergoing allogeneic HSCT for hematologic malignancies between 1996 and 2006, using pretransplantation serum ferritin as a surrogate marker of iron overload. At 5 years, patients in the high ferritin group (>or= 599 ng/mL) had a lower overall survival (OS; 33.0% versus 63.5%; P< .001) and a higher NRM (34.9% versus 13.7%; P< .001) than those in the low ferritin group (<599 ng/mL). Multivariate analyses showed that high pretransplantation serum ferritin was a significant risk factor for worse survival (relative risk [RR]=1.68; P= .05) and increased NRM (RR=2.47; P= .01). There was no significant difference in the cumulative incidence of relapse, and acute and chronic graft-versus-host disease (aGVHD, cGVHD) between the 2 groups. Patients in the high ferritin group were more likely to die of infection (P< .010) and organ failure (P< .019). Similar results were observed after dividing the patients according to the intensity of conditioning regimens. These findings emphasize the prognostic impact of pretransplantation serum ferritin in HSCT recipients.

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Successful engraftment following HLA-mismatched cord blood transplantation for patients with anti-HLA Abs

Kataoka, K., Yamamoto, G., Nannya, Y., Yoshimi, A., Okada, S., Asai, T., Kumano, K., Hangaishi, A., Takahashi, T., Chiba, S. and Kurokawa, M.

Bone Marrow Transplant 42 （ 2 ） 129 - 30 2008年07月

ISSN  0268-3369

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Recurrence of primary hyperparathyroidism following spontaneous remission with intracapsular hemorrhage of a parathyroid adenoma

Kataoka, K., Taguchi, M., Takeshita, A., Miyakawa, M. and Takeuchi, Y.

J Bone Miner Metab 26 （ 3 ） 295 - 7 2008年

ISSN  0914-8779

　概要を見る

A few patients with primary hyperparathyroidism (PHPT) have a chance of spontaneous remission by either infarction of or hemorrhage into or around the parathyroid adenoma. In most cases, biochemical derangements associated with PHPT are permanently improved after spontaneous remission. Here we report a case with a recurrence of PHPT 4 months after spontaneous remission with acute intracapsular hemorrhage of parathyroid adenoma. In the literature, only two cases have been reported to have experienced a recurrence of clinical features of PHPT after infarction but not hemorrhage of parathyroid adenomas. Thus, the spontaneous remission of biological derangements in PHPT upon hemorrhage or infarction of parathyroid adenoma could be temporary. One should carefully observe such patients thereafter.

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