Yoshihiro Hatta

Nihon University, Edo, Tokyo, Japan

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Publications (108)

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    Noriyoshi Iriyama · Bo Yuan · Yoshihiro Hatta · [...] · Masami Takei
    [Show abstract] [Hide abstract] ABSTRACT: Background: Lyn, an import member of Src family kinases (SFKs), is supposed to be implicated in acute myeloid leukemia (AML) pathogenesis and development by participation in AML differentiation, yet the details still remain incompletely understood. The expression status of Lyn and its correlation with multiple clinical parameters including cell differentiation degree, different cytogenetic risk classification, and the activity of myeloperoxidase (MPO) were thus investigated. To address the mechanisms underlying the involvement of Lyn in differentiation induction, the effects of dasatinib, an inhibitor for SFKs including Lyn, on the alterations of all-trans retinoic acid (ATRA)- or dihydroxyvitamin D3 (VD3)-induced differentiation, and c-Myc protein expression were investigated. Methods: Primary AML blasts were obtained from 31 newly diagnosed AML patients with different French-American-British (FAB) subtypes. The expression of phosphorylated and total Lyn, c-Myc, and CD11b, CD11c and CD15 was analyzed by flow cytometry. The activation of Akt and Erk known to be involved in the regulation of c-Myc expression was investigated using western blotting. Results: Significant higher expression levels of total Lyn were observed in AML patients with favorable cytogenetics, higher MPO activity and FAB M2 subtype. A clear positive correlation between the expression levels of Lyn and differentiation status of primary AML blasts was observed. Dasatinib inhibited the expression of phosphorylated Lyn, and further enhanced the differentiation-inducing activity of ATRA and VD3 in HL-60 cells. Augmented downregulation of c-Myc protein expression was observed in the combination treatment with ATRA, VD3 and dasatinib compared to treatment with each reagent alone in HL-60 cells. The suppression of the activation of Akt and Erk was also observed concomitantly. Conclusions: The expression level of total Lyn is closely linked to the differentiation status of AML blasts. The enhancement of differentiation-inducing activity of ATRA/VD3 by dasatinib suggested that Lyn was associated in the negative regulation of ATRA/VD3-induced HL-60 cells differentiation. The enhancement probably was attributed to the downregulation of c-Myc implicated with the suppression of the activation of Akt and Erk. These results provide novel insights into a possible combinational therapeutic approach by targeting Lyn for AML patients, and offer new possibilities for the combination therapy with VD3 and dasatinib.
    Full-text Article · Dec 2016 · Cancer Cell International
  • Noriyoshi Iriyama · Katsuhiro Miura · Yoshihiro Hatta · [...] · Masami Takei
    [Show abstract] [Hide abstract] ABSTRACT: In this study, the impact of plasma cell maturity on the prognoses of multiple myeloma (MM) patients in the era of novel agents was investigated. Myeloma cell maturity was classified via immunophenotyping: myeloma cells showing mature plasma cell 1 (MPC-1)-positive and CD49e-positive cells were considered mature type; MPC-1-positive and CD49e-negative cells were considered intermediate type; and MPC-1-negative cells were considered immature type. This study included 87 newly diagnosed MM patients who were initially treated with bortezomib and/or chemotherapy. Myeloma cell maturity was a critical factor affecting overall survival (OS) in the cohort, with median OS not reached in mature-type, 50 months in intermediate-type, and 20 months in immature-type cells. Multivariate analysis showed that immature type and stage III according to the International Staging System were both independent prognostic factors affecting OS. The findings of this study demonstrate the clinical importance of myeloma cell classification according to immunophenotyping using MPC-1 and CD49e antibodies to determine patient prognosis in this era of novel therapeutic agents.
    Article · Aug 2016 · Medical Oncology
  • [Show abstract] [Hide abstract] ABSTRACT: Mantle cell lymphoma (MCL) is a B cell neoplasm characterized by cyclin D1 overexpression; its prognosis is poor, especially when it exhibits a blastoid morphology. Cyclin D1-negative MCL is rare, and its pathogenesis and progression remain unclear. Herein, we describe a cyclin D1-negative, cyclin D2-positive MCL with a CCND2 and immunoglobulin lambda light chain (IGL) translocation. The patient was initially diagnosed with cyclin D1-negative MCL and achieved complete remission via combination chemotherapy and autologous stem cell transplantation. After relapsing, he was diagnosed with a blastoid variant of MCL that showed lymphoid cells with dispersed chromatin and more mitotic figures and higher p53 expression compared with the initial MCL. Despite salvage therapies, the disease became refractory, and the patient died 28 months after initiating chemotherapy. This case demonstrates that blastoid morphology in cyclin D1-negative MCL with IGL-CCND2 translocation indicates progression to a more aggressive neoplasm, similar to cyclin D1-positive MCL.
    Article · Jul 2016 · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin
  • [Show abstract] [Hide abstract] ABSTRACT: Lennert lymphoma (LeL) is a variant of peripheral T-cell lymphoma, not otherwise specified. Few clinicopathologic studies have investigated LeL, which is a rare disease. Here, we analyzed the clinicopathologic features of 26 patients with LeL to identify potential prognostic factors. Neoplastic cells positive for CD4, CD8, CD4/CD8, TIA-1, and granzyme B were observed in 21 (80.8%), 4 (15.4%), 1 (3.8%), 4 (15.3%), and 0 (0.0%) patients, respectively. Regarding follicular helper T-cell (TFH) markers, neoplastic cells positive for programmed cell death-1 (PD-1), CXCL13, CD10, and BCL6 were observed in 14 (53.8%), 13 (50.0%), 1 (3.8%), and 0 (0.0%) patients, respectively. Patients with positivity for at least 1 TFH cell marker (PD-1, CXCL13, CD10, and/or BCL6) were defined as being TFH cell marker-positive (n=15) and had a worse prognosis than TFH cell marker-negative patients (n=11) (P=0.011). Clinicopathologic characteristics did not differ significantly between TFH cell marker-positive and marker-negative LeL patients. Moreover, prognosis did not differ significantly between TFH cell marker-positive LeL patients and patients with angioimmunoblastic T-cell lymphoma (AITL) (n=42). Nevertheless, as compared with AITL, TFH cell marker-positive LeL was associated with significantly lower frequencies of B symptoms, skin rash, high-intermediate-risk or high-risk international prognostic index values, expanded follicular dendritic cell meshworks, polymorphic infiltrate, clear cells, and positivity for CD10 and BCL6. Although it may be difficult to definitively distinguish between TFH cell marker-positive LeL and AITL, our results suggest that TFH cell markers are useful for identifying LeL patients who will experience unfavorable outcomes.
    Article · Jul 2016 · American Journal of Surgical Pathology
  • [Show abstract] [Hide abstract] ABSTRACT: Co-expression of MYC and BCL2 proteins in diffuse large B-cell lymphoma (DLBCL), or 'double-expressor lymphoma' (DEL), results in poor patient prognosis, but the significance of DEL when aggressive treatments are applied remains uncertain. We performed a retrospective analysis of 40 patients with de novo DLBCL, who were categorized as being at high/high-intermediate risk according to the age-adjusted International Prognostic Index. Patients underwent an R-Double-CHOP regimen, a dose-intensified immunochemotherapy with or without consolidative high-dose chemotherapy followed by autologous stem cell transplantation. According to immunohistochemical analysis, 10 (25%) patients were categorized as having DEL, showing positivity for MYC (≥40%) and BCL2 (≥50%). The 3 year progression-free survival and overall survival of the DEL group were significantly worse compared with those of the non-DEL group (30% vs. 63%, p = 0.019 and 40% vs. 82%, p = 0.006, respectively). These results suggest that advanced DEL may need discrete treatment strategies.
    Article · Apr 2016 · Leukemia & lymphoma
  • Daisuke Kurita · Yoshihiro Hatta · Atsuko Hojo · [...] · Masami Takei
    [Show abstract] [Hide abstract] ABSTRACT: The Philadelphia chromosome (Ph) is the most frequent chromosomal abnormality detected in adult acute lymphoblastic leukemia (ALL). This chromosome forms the BCR/ABL1 fusion gene, thus ABL1 exon a2 is generally used as a primer-binding region for the detection of the fusion transcript via reverse transcription polymerase chain reaction (RT-PCR). We observed a rare case of adult Ph-positive (Ph+) ALL, in which the BCR/ABL1 fusion transcript was not detected using the ABL1 exon a2 region primer. However, we were able to isolate a PCR product by RT-PCR with the BCR exon 13 (b2) and ABL1 exon a3 primers. Analysis of the sequence of the RT-PCR product revealed that the fusion point was between BCR exon 14 (b3) and ABL1 exon a3, and that the transcript lacked ABL1 exon a2. The patient achieved cytogenetic remission through combination chemotherapies, but relapse occurred before hematopoietic stem cell transplantation and the patient died 11 months after the initialization of chemotherapies. If the BCR/ABL1 fusion transcript is undetected with the ABL1 exon a2 region primer in Ph+ ALL cases, an RT-PCR analysis that can detect the b3a3 type BCR/ABL1 fusion transcript should be considered to improve diagnosis.
    Article · Jan 2016 · Cancer Genetics
  • Katsuhiro Miura · Yoshihiro Hatta · Masami Takei
    [Show abstract] [Hide abstract] ABSTRACT: In recent years, advances in cancer immunology research have led to the development of immune checkpoint inhibitors for anticancer treatments against many types of malignant neoplasms. However, immunological approaches have already achieved great success in the treatment of hematological malignancies, due to their specificity. In this review article, we discuss hematological malignancies from the perspective of cancer immunology, along with the advancement of monoclonal antibodies since the advent of rituximab, and the development of immune checkpoint inhibitors.
    Article · Jan 2016 · Nichidai igaku zasshi
  • [Show abstract] [Hide abstract] ABSTRACT: We performed a clinical trial to investigate the efficacy and safety of arbekacin (ABK), a unique aminoglycoside with activity against methicillin-resistant Staphylococcus aureus (MRSA), in patients with hematological malignancies complicated by high-risk infections. ABK was administered intravenously at a dose of approximately 5 mg/kg with various broad-spectrum β-lactams, followed by therapeutic drug monitoring (TDM). A total of 54 febrile or infectious episodes were registered, and TDM was performed in 44 (81 %) cases. The absolute neutrophil count was below 500/μl in 49 (91 %) cases, and cytotoxic chemotherapy was being administered in 47 (87 %) cases. Before initiation of ABK, 52 (96 %) patients had received fluoroquinolones (n = 37) and/or broad-spectrum β-lactams (n = 34). There were 10 cases of documented infections including one of MRSA pneumonia, and 44 cases of febrile neutropenia. The efficacy at the end of treatment was 80 % for all patients, and efficacy was significantly higher in patients attaining maximum concentrations ≥16 µg/ml or receiving TDM-guided dose-adjustment of ABK (n = 19, 95 vs. 71 %, P = 0.039). Renal toxicity was observed in six cases (11 %) but was generally acceptable. This study demonstrated that TDM-guided ABK administration may be applicable under limited conditions for patients with hematological malignancies.
    Article · Dec 2015 · International journal of hematology
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    [Show abstract] [Hide abstract] ABSTRACT: Granulocyte colony-stimulating factor (G-CSF) promotes proliferation, survival, and differentiation of myeloid-linage leukemic cells, as well as normal hematopoietic cells. Terminal granulocytic differentiation can be induced in acute promyelocytic (APL) cell line HT93A by G-CSF and all-trans retinoic acid (ATRA). Because the detailed mechanism has never been shown, we investigated the signal transduction pathway in granulocytic differentiation by G-CSF, alone or in combination with ATRA. HT93A cell viability and growth were investigated by trypan blue exclusion assay. Cell differentiation was assessed by CD11b and CD34 expressions. Intracellular protein expressions were also evaluated by flow cytometry after fixation and permeabilization. ATRA (100 nM) induced granulocytic differentiation (upregulation of CD11b and downregulation of CD34) and the effect was potentiated by addition of G-CSF, while G-CSF alone had no effect on HT93A cells. The addition of G-CSF to ATRA had little or no effect on NB4 and THP-1 cells in comparison to ATRA alone. G-CSF receptor expression was reduced by ATRA treatment in a time-dependent manner. After 5 days' incubation with ATRA, the expression levels of signal transducer and activator of transcription (STAT) 3, and phosphorylated STAT3 and STAT5, were significantly reduced. STAT5 was strongly activated by G-CSF stimulation in ATRA-pretreated cells in comparison to untreated cells. In contrast, STAT3 showed no response to G-CSF. Janus kinase (JAK) inhibitor ruxolitinib (320 nM) had little or no effect on ATRA-induced differentiation, but eliminated the enhancing effect of G-CSF, as evidenced by the levels of CD11b and CD34 expression. These results suggest G-CSF activates STAT5 through the JAK pathway in combination with ATRA, resulting in myeloid differentiation in HT93A cells. In conclusion, activation of the JAK-STAT pathway is likely essential for inducting differentiation in the APL cell line HT93A; thus, monitoring its expression and activation is important for predicting clinical efficacy and understanding the mechanisms of cytokine-dependent myelopoiesis, proliferation, and differentiation of acute myeloid leukemia.
    Full-text Article · Dec 2015 · Cancer Cell International
  • Article · Nov 2015 · Annals of Oncology
  • [Show abstract] [Hide abstract] ABSTRACT: We have previously shown the clinical usefulness of Wilms' tumor 1 gene (WT1) mRNA expression in peripheral blood (PB) as a minimal residual disease (MRD) monitoring marker in 191 acute myeloid leukemia (AML) patients using the WT1 mRNA assay kit "Otsuka" (Otsuka Pharmaceutical Co., Ltd.; "former kit"). In contrast, the usefulness of WT1 mRNA expression in bone marrow (BM) has been investigated in only a limited number of subjects using former kit. Following that previous study, a next-generation kit, WT1 mRNA assay kit II "Otsuka" (Otsuka Pharmaceutical Co., Ltd.; "new kit") has been newly developed. In the present study, we aimed to evaluate the performance of the new kit and to investigate the clinical usefulness of WT1 mRNA expression in BM. The PB and BM were collected on the same day from 164 blood disease patients, including 118 AML patients. WT1 mRNA expression was determined using the new and former kits and the values obtained were compared. The performance of new kit was shown to be equivalent to that of former kit. As reported in PB, WT1 mRNA expression in BM was found to be a useful marker for monitoring disease status as well as for a diagnosis of early stage relapse in AML patients.
    Article · Nov 2015 · International journal of hematology
  • Tomonori Harada · Yukio Hirabayashi · Yoshihiro Hatta · [...] · Shin Aizawa
    [Show abstract] [Hide abstract] ABSTRACT: In the bone marrow, hematopoietic cells proliferate and differentiate in close association with a three-dimensional (3D) hematopoietic microenvironment. Previously, we established a 3D bone marrow culture system. In this study, we analyzed the kinetics of hematopoietic cells, and more than 50% of hematopoietic progenitor cells, including CFU-Mix, CFU-GM and BFU-E in 3D culture were in a resting (non-S) phase. Furthermore, we examined the hematopoietic supportive ability of stromal cells by measuring the expression of various mRNAs relevant to hematopoietic regulation. Over the 4 weeks of culture, the stromal cells in the 3D culture are not needlessly activated and "quietly" regulate hematopoietic cell proliferation and differentiation during the culture, resulting in the presence of resting hematopoietic stem cells in the 3D culture for a long time. Thus, the 3D culture system may be a new tool for investigating hematopoietic stem cell-stromal cell interactions in vitro.
    Article · Oct 2015 · Growth factors (Chur, Switzerland)
  • Noriyoshi Iriyama · Yoshihiro Hatta · Sumiko Kobayashi · [...] · Masami Takei
    [Show abstract] [Hide abstract] ABSTRACT: The significance of red blood cell distribution width (RDW) was evaluated in patients with chronic myeloid leukemia (CML) in the chronic phase (CP). Eighty-four patients with newly-diagnosed CML-CP treated with any tyrosine kinase inhibitor (TKI) were analyzed. Patients were divided into two groups: a low-RDW group (RDW values ≤15%, n=31) and a high-RDW group (RDW values >15%, n=53). The 5-year event-free survival (EFS) and transformation-free survival (TFS) rates differed significantly between the low- and high-RDW groups (100% and 68%, respectively, in EFS, p=0.0071 and 100% and 81%, respectively, in TFS, p=0.039). The stratification by RDW had an impact on overall 5-year survival (100% in the low and 77% in the high RDW groups, p=0.047). We conclude that the RDW has a critical role in risk stratification of CML-CP patients for predicting treatment responses and outcomes.
    Article · Oct 2015 · Anticancer research
  • [Show abstract] [Hide abstract] ABSTRACT: The clinical significance of concurrent expression of MYC and BCL2 protein, known as "double-expressor lymphoma" (DEL), among patients with relapsed or refractory aggressive B-cell lymphomas remains unclear. We performed a retrospective analysis of 38 patients treated with a salvage treatment consisting of rituximab, ifosfamide, etoposide, cytarabine and dexamethasone followed by consolidative high-dose chemotherapies. A total of 17 cases (45%) were categorized as DEL using immunohistochemical assay with a cut-off value of positivity of 40% for MYC and 50% for BCL2, respectively. DEL was associated with a lower overall response rate (35% vs 71%, p = 0.0481), worse 2-year progression-free survival (9% vs 67%, p = 0.001), and overall survival (35% vs 71%, p = 0.037). This analysis suggests that DEL is common among patients with relapsed/refractory aggressive B-cell lymphomas, and that such patients require novel treatment strategies.
    Article · Sep 2015 · Leukemia & lymphoma
  • [Show abstract] [Hide abstract] ABSTRACT: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare tumor that usually arises in the skin. Most patients develop skin lesions, which may be isolated and subsequently spread to affect the whole body. The prognosis is poor. Although BPDCN is usually treated by chemotherapy, radiation therapy is used in some cases (e.g., isolated lesions, elderly patients, or patients with comorbidities). The overall therapeutic efficacy and dose of radiation therapy remain unknown. We herein present a case of successful radiation treatment for BPDCN in a 77-year-old Japanese patient and describe the results of the first literature review on BPDCN of the skin initially treated with radiation therapy. The patient developed a raised, tender, pruritic skin lesion on his left forearm and similar multiple disseminated lesions on his right shoulder and precordial region. Histological and immunohistochemical examination of biopsy specimens of the skin lesions on the left forearm and right shoulder established a diagnosis of BPDCN. The other multiple skin lesions were considered to be disseminated BPDCN. The patient declined chemotherapy and instead elected radiation therapy for the lesion on his left forearm (total of 30 Gy). The skin lesion regressed until only pigmentation was present on the forearm, but the untreated lesions rapidly expanded. Although BPDCN of the skin may respond favorably to initial radiation therapy, it tends to recur in the short term. The optimal dose of radiation therapy remains unclear. Our findings provide a baseline for future research.
    Article · Jul 2015 · International Journal of Clinical and Experimental Medicine
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    [Show abstract] [Hide abstract] ABSTRACT: Even after the advent of rituximab, clinical outcomes of conventional immuno-chemotherapy for high-risk diffuse large B-cell lymphoma (DLBCL) remain unsatisfactory. We retrospectively evaluated the efficacy and safety of R-Double-CHOP (R-D-CHOP), consisting of rituximab (375 mg/m(2), day -2), cyclophosphamide (750 mg/m(2), day 1, 2), doxorubicin (50 mg/m(2), day 1, 2), vincristine [1.4 mg/m(2) (maximum 2.0 mg/body), day 1], and prednisolone (50 mg/m(2), day 1-5), followed by consolidation high-dose chemotherapy. This treatment was given to 51 de novo DLBCL patients with a median age of 54 (range 19-65), who were categorized as high/high-intermediate risk by the age-adjusted International Prognostic Index. Treatment was given every 3 weeks up to three courses. The overall response and the complete response rate for R-D-CHOP were 94 and 78 %, respectively. A total of 30 responders proceeded to high-dose chemotherapy followed by autologous stem cell transplantation (HDC/ASCT), whereas 16 received high-dose methotrexate (HD-MTX) alternatively. The 3-year overall survival and the event-free survival for all patients were 78 and 61 %, respectively. Major adverse events included hematological toxicities, but there were no treatment-related deaths during the observation period. We conclude that the R-D-CHOP regimen followed by HDC/ASCT or HD-MTX is a promising treatment option for younger patients with highly advanced DLBCL.
    Full-text Article · Mar 2015 · International Journal of Hematology
  • [Show abstract] [Hide abstract] ABSTRACT: Dasatinib is a BCR-ABL kinase inhibitor with improved potency compared with imatinib, for which efficacy and safety in imatinib-resistant and imatinib-intolerant patients with chronic myelogenous leukemia (CML) have been established. Here, an open-label phase II study evaluated the efficacy and safety of dasatinib in 50 Japanese patients with imatinib-resistant or imatinib-intolerant CML during the chronic phase (CML-CP). Dasatinib was effective in imatinib-resistant and imatinib-intolerant patients. After 12 months of dasatinib therapy, 35 patients (70%) had achieved a major molecular response (MMR) and 16 patients (32%) had achieved a complete molecular response (CMR). Among the imatinib-resistant CML-CP cohort, 21 and 8 patients had achieved an MMR and a CMR after 12 months of dasatinib therapy, respectively. Among the imatinib-intolerant CML-CP cohort, 14 and 8 patients had achieved an MMR and a CMR after 12 months of dasatinib therapy, respectively. After 18 months of dasatinib therapy, 38 out of 50 patients (76.0%) had achieved an MMR and 19 patients (38.0%) had achieved a CMR. A lower level of BCR-ABL transcript at 1 or 3 months after the initiation of dasatinib treatment was more strongly correlated with the BCR-ABL transcript level at 12 and 18 months (p < 0.001) than a higher level of BCR-ABL. The T315I mutation was identified in two patients receiving dasatinib therapy. Dasatinib was generally well tolerated, with only 3 patients (5%) having treatment discontinuation as a result of adverse hematologic events (thrombocytopenia, anemia, neutropenia) and/or non-hematologic events at a 12-month follow-up evaluation. Dasatinib was a safe and effective treatment for Japanese patients with imatinib-resistant or imatinib-intolerant CML. In addition, the molecular response at 1 or 3 months predicted a response to dasatinib at 12 or 18 months.
    Article · Dec 2014 · Journal of Clinical and Experimental Hematopathology
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    Hiromichi Takahashi · Yoshihiro Hatta · Noriyoshi Iriyama · [...] · Masami Takei
    [Show abstract] [Hide abstract] ABSTRACT: Retinoids and 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) induce differentiation of myeloid leukemia cells into granulocyte and macrophage lineages, respectively. All-trans retinoic acid (ATRA), which is effective in the treatment of acute promyelocytic leukemia, can induce differentiation of other types of myeloid leukemia cells, and combined treatment with retinoid and 1,25(OH)2D3 effectively enhances the differentiation of leukemia cells into macrophage-like cells. Recent work has classified macrophages into M1 and M2 types. In this study, we investigated the effect of combined treatment with retinoid and 1,25(OH)2D3 on differentiation of myeloid leukemia THP-1 and HL60 cells. 9-cis Retinoic acid (9cRA) plus 1,25(OH)2D3 inhibited proliferation of THP-1 and HL60 cells and increased myeloid differentiation markers including nitroblue tetrazolium reducing activity and expression of CD14 and CD11b. ATRA and the synthetic retinoic acid receptor agonist Am80 exhibited similar effects in combination with 1,25(OH)2D3 but less effectively than 9cRA, while the retinoid X receptor agonist HX630 was not effective. 9cRA plus 1,25(OH)2D3 effectively increased expression of M2 macrophage marker genes, such as CD163, ARG1 and IL10, increased surface CD163 expression, and induced interleukin-10 secretion in myeloid leukemia cells, while 9cRA alone had weaker effects on these phenotypes and 1,25(OH)2D3 was not effective. Taken together, our results demonstrate selective induction of M2 macrophage markers in human myeloid leukemia cells by combined treatment with 9cRA and 1,25(OH)2D3.
    Full-text Article · Nov 2014 · PLoS ONE
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    Noriyoshi Iriyama · Yoshihiro Hatta · Masami Takei
    [Show abstract] [Hide abstract] ABSTRACT: Abstract We investigated the role of ETV6/ARG fusion genes by exposing the HT93A cell line to nilotinib. HT93A cells were cultured with or without nilotinib ± 50 ng/ml of granulocyte colony-stimulating factor (G-CSF). Nilotinib treatment inhibited cell growth by increasing the percentage of cells in the G0/G1 phase through the decrease of phosphorylated STAT3 (Y705), STAT5 (Y694), and c-Myc expression. After stimulation with G-CSF, STAT5 but not STAT3 was significantly phosphorylated in both nilotinib-treated and untreated cells. Moreover, combination therapy with nilotinib and G-CSF returned the expression level of c-Myc, cell growth, and cell cycle distribution to the control level. These findings suggest that the ETV6/ARG oncoprotein contributes to autonomous cell growth by compensating for the requirement of growth factor through activating STAT5 signaling, which leads to the upregulation of c-Myc. Our data suggest that ETV6/ARG oncoprotein is a potential target in the treatment of leukemia.
    Full-text Article · Nov 2014 · Leukemia and Lymphoma
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    [Show abstract] [Hide abstract] ABSTRACT: Purpose: The introduction of all-trans-retinoic acid (ATRA) has significantly improved outcomes for acute promyelocytic leukemia (APL), although a subset of patients still suffer relapse. The purpose of this study was to evaluate the role of maintenance therapy with the synthetic retinoid tamibarotene in APL. Patients and methods: Patients with newly diagnosed APL in molecular remission at the end of consolidation therapy were randomly assigned to receive ATRA or tamibarotene, both orally, for 14 days every 3 months for up to 2 years. Results: A total of 347 patients were enrolled. Of the 344 eligible patients, 319 (93%) achieved complete remission. After completing three courses of consolidation therapy, 269 patients underwent maintenance random assignment. The relapse-free survival (RFS) rate at 4 years was 84% for the ATRA arm and 91% for the tamibarotene arm (hazard ratio [HR], 0.54; 95% CI, 0.26 to 1.13). When the analysis was restricted to 52 high-risk patients with an initial WBC count ≥ 10.0 × 10(9)/L, the intergroup difference was statistically significant, with 4-year RFS rates of 58% for the ATRA arm and 87% for the tamibarotene arm (HR, 0.26; 95% CI, 0.07 to 0.95). For patients with non-high-risk disease, the HR was 0.82 (95% CI, 0.32 to 2.01). The test for interaction between treatment effects and these subgroups resulted in P = .075. Both treatments were generally well tolerated. Conclusion: In this trial, no difference was detected between ATRA and tamibarotene for maintenance therapy. In an exploratory analysis, there was a suggestion of improved efficacy of tamibarotene in high-risk patients, but this requires further study.
    Full-text Article · Sep 2014 · Journal of Clinical Oncology