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ABSTRACT: Some chronic myeloid leukemia (CML) patients with a sustained complete molecular response (CMR) for at least 2 years during imatinib (IM) therapy can discontinue IM without relapse. With the long-term goal of developing immunological criteria for managing IM therapy in CML patients, we compared the immunophenotypic profiles of three groups of CML patients: patients who received IM and had a CMR for more than 2 consecutive years (CMR group); patients who received IM and did not have a sustained CMR but maintained a major molecular response for more than 2 years (fluctuating CMR group); and patients with a sustained CMR for more than 6 months after IM discontinuation (STOP-IM group), together with healthy controls. The percentages of effector populations of natural killer (NK) cells, such as interferon (IFN)-γ(+) CD3(-) CD56(+) cells, were significantly higher in the STOP-IM and CMR groups than in the fluctuating CMR and control groups. The elevated levels of these effector NK cells were sustained for more than 3 years after IM discontinuation. In contrast, the percentages of effector memory CD8(+) T cells, such as IFN-γ(+) CCR7(-) CD45RO(+) CD8(+) cells, were significantly higher in the STOP-IM and control groups than in the CMR and fluctuating CMR groups, possibly owing to IM intake. These results suggest that the immunological activation status of NK cells contributes to CMR maintenance. Higher activation levels of effector NK cells in CML patients being treated with IM might reflect minimization of BCR-ABL1 transcript levels and therefore might be an additive information for determining whether to stop IM. This article is protected by copyright. All rights reserved.
Cancer Science 06/2013; · 3.33 Impact Factor
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ABSTRACT: Mixed-lineage leukemia (MLL)/AF4-positive acute lymphoblastic leukemia (ALL) is a common type of leukemia in infants, which is associated with a high relapse rate and poor prognosis. IL24 selectively induces apoptosis in cancer cells and exerts immunomodulatory and antiangiogenic effects. We examined the effects of adeno-associated virus type 8 (AAV8) vector-mediated muscle-directed systemic gene therapy in MLL/AF4-positive ALL using IL24. In a series of in vitro studies, we examined the effects of AAV8-IL24-transduced C2C12 cell-conditioned medium. We also examined the effects of AAV8-IL24 in MLL/AF4 transgenic mice. The results revealed the effects of AAV8-IL24 in MLL/AF4-positive ALL both in vitro and in vivo. With regard to the mechanism of therapy using AAV8-IL24 in MLL/AF4-positive ALL, we demonstrated the antiangiogenicity and effects on the ER stress pathway and unreported pathways through inhibition of S100A6 and HOXA9, which is specific to MLL/AF4-positive ALL. Inhibition of S100A6 by IL24 was dependent on TNF-α and induced acetylation of p53 followed by activation of the caspase 8-caspase 3 apoptotic pathway. Inhibition of HOXA9 by IL24, which was independent of TNF-α, induced MEIS1 activation followed by activation of the caspase 8-caspase 3 apoptotic pathway. Thus, gene therapy using AAV8-IL24 is a promising treatment for MLL/AF4-positive ALL.
Blood 01/2012; 119(1):64-71. · 9.90 Impact Factor
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Journal of Clinical and Experimental Hematopathology 01/2012; 52(2):145-7.
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Chikashi Yoshida,
Linda Fletcher,
Kazuteru Ohashi,
Hisashi Wakita,
Takashi Kumagai,
Masayuki Shiseki,
Kousei Matsuei, Koiti Inokuchi,
Yoshihiro Hatta,
Yukari Shirasugi,
Toshikazu Yamaguchi,
Junichi Sakamoto,
Susan Branford,
Hisashi Sakamaki
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ABSTRACT: BACKGROUND: Real-time quantitative polymerase chain reaction (RQ-PCR) has been widely used for molecular monitoring for patients with chronic myeloid leukemia (CML). Currently, RQ-PCR is not based on the concept of international scale (IS) in Japan; mainly because none of the domestic laboratories have obtained their own conversion factor (CF) which makes it possible to convert locally scaled BCR-ABL (BCR-ABL (L)) value to the IS (BCR-ABL (IS)). To join the global trend of molecular assessment of BCR-ABL in CML patients, we have tried to obtain a CF in Japan. METHODS: Samples from 55 patients were exchanged between the Japanese laboratory and the reference laboratory in Adelaide, and BCR-ABL and internal control gene transcripts of the samples were measured using RQ-PCR. The patient bias conversion method was used to determine the CF for the IS using the Bland and Altman method. RESULTS: The local CF in the Japanese laboratory was determined to be 0.87. Based on this CF, 0.1% BCR-ABL (IS), defined as major molecular response, becomes equivalent to 731 copy/μg RNA BCR-ABL (L). CONCLUSION: This study is the first to introduce a laboratory-specific CF for harmonizing RQ-PCR methodology for detecting BCR-ABL transcripts to Japan, which may open new windows for molecular assessment of CML patients in Japan.
International Journal of Clinical Oncology 10/2011; · 1.41 Impact Factor
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ABSTRACT: Recently, RCSD1 was identified as a novel gene fusion partner of the ABL1 gene. The RCSD1 gene, located at 1q23, is involved in t(1;9)(q23;q34) translocation in acute B lymphoblastic leukemia. Here we describe RCSD1-ABL1-positive B-cell acute lymphoblastic leukemia (ALL) followed by rapid clonal evolution exhibiting three rare reciprocal translocations. We performed breakpoint analysis of the transcript expressed by the RCSD1-ABL1 fusion gene. RT-PCR and sequence analyses detected transcription of a single RCSD1-ABL1 fusion gene variant, which had breakpoints in exon 3 of RCSD1 and exon 4 of ABL1. The RCSD1 portion of the RCSD1-ABL1 fusion transcript consists of exons 1, 2, and 3. Tyrosine kinase inhibitors, imatinib and dasatinib, coadministered with dexamethasone achieved transient clinical effects in the present RCSD1-ABL1-positive ALL. However, leukemic cells rapidly became refractory to this treatment following the subsequent development of three additional reciprocal chromosomal translocations, t(5;16)(q33;q24), dic(18;20)(p11.2;q11.2) and t(10;19)(q24;p13.3). The present RCSD1-ABL1-positive ALL may represent a state of high chromosomal instability.
International journal of hematology 08/2011; 94(3):255-60. · 1.17 Impact Factor
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European Journal Of Haematology 02/2011; 86(2):180-1. · 2.61 Impact Factor
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ABSTRACT: CHOP therapy combined with rituximab (R-CHOP) is currently a standard chemotherapy for diffuse large B-cell lymphoma (DLBCL). However, relapse is detected despite R-CHOP in approximately 30% of patients. Treatment results should be further improved. Previously, second- and third-generation therapies such as MACOP-B, m-BACOD, and ProMACE-CytaBOM were performed to improve the results of DLBCL treatment. However, dose intensity (DI) enhancement increased treatment-associated toxicity, and the treatment results did not improve. Recently, the entity of the relative dose intensity (RDI) was proposed as an index of the intensity of chemotherapy. In this method, the ratio of actual DI to the DI designed per specific period is numerically evaluated. The purpose of calculating the RDI is to achieve chemotherapy as scheduled while maintaining the DI, and not to improve the DI. Previous studies reported that the maintenance of the RDI during CHOP therapy improved the treatment results. In this paper, we review DI and RDI in studies of DLBCL, and revisit the significance of these indicators.
Journal of Clinical and Experimental Hematopathology 01/2011; 51(1):1-5.
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Tetsuzo Tauchi,
Masahiro Kizaki,
Shinichiro Okamoto,
Hideo Tanaka,
Mitsune Tanimoto, Koiti Inokuchi,
Tohru Murayama,
Yoshio Saburi,
Masayuki Hino,
Mitsuru Tsudo,
Taizo Shimomura,
Yasushi Isobe,
Kazuo Oshimi,
Kazuo Dan,
Kazuma Ohyashiki,
Yasuo Ikeda
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ABSTRACT: The TARGET system is an online database that can be easily accessed by physicians. The registration of one's own chronic myeloid leukemia (CML) patients in the TARGET system makes it possible to share experiences among physicians, and, thus, may facilitate appropriate treatment for patients. Patients were registered in the TARGET system from October 2003 to March 2010 in Japan. A total of 1236 patients from 176 hospitals were registered in Japan. We analyzed data from 639 CML chronic phase patients not receiving prior therapy registered in this system. After 90 months follow-up, high survival rates were demonstrated for imatinib-treated newly diagnosed CML patients, with event-free survival (EFS), progression-free survival (PFS), and overall survival (OS) rates of 79.1, 94.8, and 95.1%, respectively. A landmark analysis of 296 patients who showed a complete cytogenetic response (CCyR) at 12 months after the initiation of imatinib treatment revealed that, at 90 months, 99% of patients (95% CI, 98-100) had not progressed to accelerated phase (AP) or blastic crisis (BC). The patients showing a CCyR and a reduction of at least 3log levels of BCR-ABL transcripts after 18 months of treatment had an estimated survival rate without CML progression of 100% at 84 months. The probability of achieving undetectable BCR-ABL in patients by 72 months with an major molecular response (MMR) at 12 months was 86.5%, compared with 64.7% for those without an MMR (p < 0.0001). There were no new safety issues. In summary, based on this 7-year TARGET analysis, imatinib showed a continual clinical benefit as first-line therapy for newly diagnosed CML. The TARGET system may represent a more practical and general feature compared with the IRIS study.
Leukemia research 12/2010; 35(5):585-90. · 2.36 Impact Factor
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British Journal of Haematology 09/2010; 150(6):725-7. · 4.94 Impact Factor
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ABSTRACT: CHOP-like regimen combined with rituximab is a standard chemotherapy for diffuse large B-cell lymphoma (DLBCL). The relative dose intensity (RDI) was proposed as an index of the dose and administration interval of agents. Previous studies reported that the maintenance of the RDI during CHOP therapy improved the treatment results. However, few studies regarding RDI have reviewed patients receiving combination therapy with CHOP and rituximab. We investigated the influence of RDI maintenance, involving combination therapy with rituximab, on therapeutic effects in patients with DLBCL. We retrospectively examined 152 DLBCL patients who were treated with CHOP-like regimen combined with rituximab in whom the RDI could be followed up. Multivariate analysis revealed that international prognosis index (IPI) high intermediate-high (HI-H) (p = 0.005) and RDI of less than 70% (p = 0.007) were independent prognostic factors for low progression free survival. Concerning overall survival, IPI HI-H (p = 0.027) and an RDI of less than 70% (p = 0.002) were involved in an unfavorable prognosis. In addition, age over 60 years (p = 0.003), R-THPCOP (p = 0.034), or the presence of febrile neutropenia (p = 0.004) made RDI maintenance difficult, and prophylactic G-CSF therapy (p = 0.026) was useful for maintaining the RDI. Maintaining the RDI is important even in the era of rituximab-combined chemotherapy for DLBCL.
Annals of Hematology 04/2010; 89(9):897-904. · 2.62 Impact Factor
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ABSTRACT: Rearrangements of the MLL gene located at 11q23 are common chromosomal abnormalities associated with acute leukemia (AL), especially infant and secondary leukemia after previous treatment with DNA topoisomerase II inhibitors. 11q23/MLL abnormalities have been widely recognized as an important prognostic factor in AL. Over 70 chromosome partners of 11q23 have been identified to date, at least 50 of which have been cloned and characterized at the molecular level. Recent studies showed that the prognosis of 11q23/MLL AL varies widely according to the partner gene, the leukemia cell lineage, the age of the patient and the treatment administered. Special strategies are needed to treat 11q23/MLL AL, including allogeneic hematopoietic stem cell transplantation, according to the fusion partner. The development of novel methodologies, including new molecular therapeutic targets, is also needed to improve the prognosis of 11q23/MLL AL. The present article provides an update on the current status of prognosis and treatment of 11q23/MLL AL according to the fusion partner.
Journal of Clinical and Experimental Hematopathology 01/2010; 50(2):91-8.
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ABSTRACT: Recently several different JAK2 exon12 mutations have been identified in V617F negative polycythaemia vera (PV) or idiopathic erythrocytosis (IE) patients. The patients present with erythrocytosis, ligand-independent cell growth and low serum erythropoietin (EPO) levels. Within this group, a deletion of amino acids 542-543 (N542-E543del) of JAK2 is most prevalent. We have previously shown that in the presence of JAK2(V617F), suppressor of cytokine signalling 3 (SOCS3) is unable to negatively regulate EPO signalling and proliferation of V617F-expressing cells. Here we report a PV patient heterozygous for the somatic JAK2(N542-E543del) mutation and a previously unreported germline mutation within the SH2 domain of SOCS3 (F136L). Interestingly, the SOCS3(F136L) mutation was detected in a Japanese myeloproliferative disorder patient cohort at double the frequency of healthy controls. Cells expressing SOCS3(F136L) had markedly elevated EPO-induced proliferation and extended EPO-induced JAK2 phosphorylation. Additionally, compared to wild-type SOCS3, mutant SOCS3 had an extended half-life in the presence of JAK2 and JAK2(N542-E543del). Our findings suggest that this loss-of-function SOCS3 mutation may have contributed to disease onset by causing deregulated JAK2 signalling in the presence of a constitutively active JAK2(N542-E543del) mutant.
British Journal of Haematology 10/2009; 147(4):450-8. · 4.94 Impact Factor
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International journal of hematology 10/2009; 90(5):651-2. · 1.17 Impact Factor
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ABSTRACT: The 11q23 abnormalities are frequent cytogenetic abnormalities found in some adult and pediatric cases of primary acute leukemia (AL), and also in the majority of patients with secondary AL after previous treatment with DNA topoisomerase II inhibitors. According to the WHO classification, AL with 11q23 abnormalities involving the Mixed- Lineage-Leukemia (MLL) gene composes one category of recurring genetic abnormalities. Over 60 chromosome partners of 11q23 have been reported to date, and 33 of the presumptive gene partners of 11q23 have been cloned and analyzed at the molecular level. 11q23/MLL abnormalities have been widely recognized as an important prognosis factor in AL. Recent studies showed that the prognosis of AL with 11q23/MLL is dependent on 11q23 fusion partner, and that the prognosis of AL with 11q23/MLL according to the 11q23 fusion partner is different between adults and children. The present article summarizes the current status of prognosis and treatment of AL with 11q23/MLL according to the fusion partner especially in adult, in which prognosis analysis has not be fully established due to a small number of cases, compared with infant cases.
Current Cancer Therapy Reviews 07/2009; 5(3):227-231.
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ABSTRACT: Concerning MLL-AF4 leukemogenesis, previous mouse models suggest that the tumorigenesis capacity of MLL-AF4 alone is insufficient for causing leukemia. Based on the finding that an Fms-like tyrosine kinase 3 (Flt3) gene mutation in the tyrosine kinase domain (TKD) was observed in approximately 15% of mixed lineage leukemia (MLL), we investigated synergistic leukemogenesis effects of the two genes in vitro.
In a mouse interleukin-3 (IL-3)-dependent cell line, 32Dc, expression of MLL-AF4 and mutant Flt3 was induced using a lentiviral vector. We analyzed apoptosis induction in the absence of IL-3 and the granulocyte colony-stimulating factor-related induction of differentiation, gene expression profiling, and the mechanism involved in the synergistic effects of MLL-AF4 and Flt3-TKD.
Neither Flt3-expressing 32Dc (32Dc(Flt3-TKD)) nor MLL-AF4-expressing 32Dc (32Dc(MLL-AF4)) acquired IL-3-independent proliferative capacity in semisolid/liquid media. However, Flt3-TKD+MLL-AF4-expressing 32Dc (32Dc(Flt3-TKD+MLL-AF4)) acquired a non-IL-3-dependent proliferative capacity by inhibiting apoptosis in the two media. The 32Dc(Flt3-TKD) and 32Dc(MLL-AF4) cells differentiated into granulocytes in the presence of granulocyte colony-stimulating factor. However, in the 32Dc(Flt3-TKD+MLL-AF4) cells, there was no differentiation. Subsequently, we performed gene expression profiling. The enhancement of Hox genes expression was not identified. However, expression of S100A6 was synergistically enhanced in the presence of both MLL-AF4 and Flt3-TKD genes. Moreover, anti-S100A6 small interfering RNA downregulated leukemic proliferation.
We conclude that their synergistic enhancement of S100A6 expression plays an important role in MLL-AF4-associated leukemogenesis.
Experimental hematology 07/2009; 37(6):701-14. · 3.11 Impact Factor
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ABSTRACT: The BCR/ABL fusion oncogene found in Philadelphia-positive leukemia exists in three principle forms: p190, p210 and p230. P210 BCR/ABL is commonly found in patients with chronic myelogenous leukemia (CML) and is further categorized into b3a2 or b2a2 subtypes on the basis of the BCR breakpoint. Although these 2 subtypes may be clinically heterogeneous, only the b3a2 BCR/ABL gene has been extensively studied at the molecular and cellular levels. In the present study, we compared the in vivo leukemogenic activity of the b3a2 and b2a2 BCR/ABL genes by using lentiviral transduction/transplantation mouse models. Lineage-depleted bone marrow cells of BALB/c mice were transduced with a lentiviral vector including either b2a2 or b3a2 BCR/ABL cDNA and then transplanted into lethally irradiated mice. In this model, p210 BCR/ABL subtype developed only B220(+), CD3e(-), Gr1(-), and Mac1(-) B-cell acute lymphoblastic leukemia but not myeloid leukemia. There were no differences in the incidence of leukemogenesis, the white blood cell count, the percentage of blast cells, or the survival rates between the b2a2 and b3a2 groups. We have demonstrated that b2a2-type BCR/ABL has leukemogenic activity similar to that of b3a2-type BCR/ABL.
Journal of Nippon Medical School 07/2009; 76(3):134-47.
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Leukemia research 04/2009; 33(8):e106. · 2.36 Impact Factor
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Muneo Okamoto,
Hiroki Yamaguchi,
Yasushi Isobe,
Norio Yokose,
Taro Mizuki,
Kenji Tajika,
Seiji Gomi,
Hiroyuki Hamaguchi, Koiti Inokuchi,
Kazuo Oshimi,
Kazuo Dan
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ABSTRACT: Secondary hemophagocytic syndrome (hemophagocytic lymphohistiocytosis, HLH) follows viral infection, malignant disorders, and autoimmune disease. Criteria for HLH diagnosis, which were proposed in 2004, include hypertriglyceridemia. However, some studies reported the absence of hypertriglyceridemia in patients with secondary HLH, differing from those with primary HLH.
In this study, we investigated the presence or absence of hypertriglyceridemia in 28 patients who were diagnosed with secondary HLH between 1997 and 2007 retrospectively. There were no patients undergoing treatment for those with a history of hyperlipidemia.
The subjects consisted of 14 patients with lymphoma-associated HLH, 11 with virus-associated HLH, 2 with autoimmune disease-associated HLH, and 1 with post transplantation HLH. In 19 patients (68%), hypertriglyceridemia was noted on diagnosis or during the disease period (mean: 242 mg/dL). Furthermore, the triglyceride (TG) level decreased with the treatment-related amelioration of HLH (mean level before and after treatment: 297 and 136 mg/dL, respectively, p=0.0001).
These results suggest that the TG level is useful for diagnosing HLH and evaluating the treatment response. TG measurement is simple and inexpensive; therefore, this parameter can be determined several times to evaluate the treatment response.
Internal Medicine 02/2009; 48(10):775-81. · 0.94 Impact Factor
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Annals of Hematology 01/2009; 88(7):705-7. · 2.62 Impact Factor
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Masahiro Kizaki,
Shinichiro Okamoto,
Tetsuzo Tauchi,
Hideo Tanaka,
Mitsune Tanimoto, Koiti Inokuchi,
Tohru Murayama,
Yoshio Saburi,
Masayuki Hino,
Mitsuru Tsudo,
Taizo Shimomura,
Yasushi Isobe
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ABSTRACT: Since hematology is a highly specialized field, an individual physician may not have much direct treatment experience with a given disease. Therefore, the Japanese Society of Hematology (JSH) has discussed establishing a registry of hematologic disorders, in order to contribute to improving the quality of treatments and clinical outcomes in this field. As a first step, the Timely and Appropriate Registration System for GLIVEC Therapy (TARGET), a registration system for chronic myeloid leukemia (CML) patients treated with imatinib, was established in October 2003. We present the preliminary results of the first 4 years' experience with this system. CML patients treated with imatinib in Japan were registered through the website and the patient's clinical course, including parameters and events like imatinib dose, blood counts, adverse events, and efficacy were recorded in months 1, 3, 6, 9, and 12 and then every 6 months thereafter. By September 2007, 862 patients from 176 hospitals were registered. Follow-up period was 0-54 months, and 127 patients were followed-up for more than 36 months. Based on these cumulative data, present imatinib treatment trends were analyzed and safety and efficacy were compared with international trial data.
International journal of hematology 11/2008; 88(4):409-17. · 1.17 Impact Factor
