Fulminant hepatitis in a hepatitis B surface antigen-positive patient with adult T-cell leukemia-lymphoma after mogamulizumab monotherapy.

We report a case of fulminant hepatitis in a hepatitis B surface antigen (HBsAg)-positive patient with aggressive adult T-cell leukemia-lymphoma who received monotherapy with an anti-CCR4 monoclonal antibody, mogamulizumab, with decreased hepatitis B virus (HBV)- DNA levels by entecavir prophylaxis. Although HBV reactivation-related hepatitis was considered in the differential diagnosis, the patient did not meet the conventional criteria for HBV reactivation and was finally diagnosed with drug-induced hepatitis. Considering that the immunoenhancing effects of mogamulizumab can lead to HBV reactivation-related hepatitis in HBsAg-positive patients, we should differentiate drug-induced hepatitis from HBV reactivation, especially in patients receiving immunomodulatory drugs, if HBV-DNA levels are reduced by antiviral prophylaxis.

Aberrant tryptophan metabolism leads to unfavorable outcomes in lenalidomide-treated myeloma patients.

Indoleamine 2,3-dioxygenase 1 (IDO), an enzyme that metabolizes tryptophan (Trp) to kynurenine (Kyn), is an important microenvironmental factor suppressing antitumor immunity. Here, we investigated the clinical impact of aberrant Trp metabolism in patients with multiple myeloma (MM) treated with lenalidomide (Len) and evaluated its effects on T cell immunity ex vivo. Kyn and Trp concentrations were quantified in sera from 72 patients with relapsed or refractory MM prior to the initiation of therapy with Len plus dexamethasone (Ld). Associations of the Kyn/Trp ratio with progression-free survival (PFS) and overall survival (OS) were analyzed. The expressions of IDO in tumor and stromal cells were evaluated during co-culture, and the effects of culture medium containing low Trp and high Kyn concentrations on T cells in the presence of Len were investigated. Patients with high serum Kyn/Trp ratios (≥46.0, n = 22) had significantly shorter PFS and OS than those with low ratios (4.9 vs. 12.6 months, and 15.5 vs. 45.7 months, respectively). MM cells promoted IDO expression in stromal cells during co-culture in both a direct contact and an indirect manner. Incubation in medium with a high Kyn/Trp ratio significantly inhibited T cell cytokine production and upregulated the expression of inhibitory immune receptors. These effects were sustained even in the presence of Len. In conclusion, a high serum Kyn/Trp ratio is associated with poor prognosis in patients with MM. We propose that aberrant Trp metabolism reduces anti-tumor immunity and the efficacy of Len therapy.

Management of hepatitis B virus (HBV) reactivation in patients with resolved HBV infection based on a highly sensitive HB core-related antigen assay.

AIMS: To prevent hepatitis B virus (HBV) reactivation-related hepatitis, we examined the clinical usefulness of a highly sensitive HB core-related antigen (iTACT-HBcrAg) assay in patients with resolved HBV infection after nucleos(t)ide analog (NA) treatment for HBV reactivation. METHODS: We retrospectively analyzed 27 patients with resolved HBV infection who experienced HBV reactivation (defined as HBV DNA levels of 1.3 log IU/ml or more), and who received systemic chemotherapies for hematological malignancies between 2008 and 2020. iTACT-HBcrAg, HBsAg-HQ, and antibodies against hepatitis B surface antigen (anti-HBs) were measured using samples stored after HBV reactivation. The lower limit of quantification for iTACT-HBcrAg was 2.0 log U/ml. RESULTS: HBV reactivation was diagnosed at a median HBV DNA level of 1.8 log IU/ml, and then all patients received NA treatment. No patient had HBV-related hepatitis with a median maximum HBV DNA level of 2.0 log IU/ml. The positivities of iTACT-HBcrAg and HBsAg-HQ were 96% and 52% after HBV reactivation, respectively. Of 25 patients with detectable iTACT-HBcrAg at the initiation of NA treatment, 17 (68%) achieved iTACT-HBcrAg loss. Median durations from NA treatment to HBV DNA loss and iTACT-HBcrAg loss or the last follow-up were 35 and 175 days, respectively. Recurrence of HBV reactivation after NA cessation was not observed in seven of eight patients who achieved iTACT-HBcrAg loss or seropositive for anti-HBs during follow-up, except for one without anti-HBs after allogeneic transplantation. CONCLUSIONS: iTACT-HBcrAg could be a potential surrogate marker for diagnosing early-stage HBV reactivation as well as safe cessation of NA treatment in patients with resolved HBV infection after HBV reactivation.

Autoantibodies in Japanese patients with ocular myasthenia gravis.

INTRODUCTION: The majority of patients with myasthenia gravis (MG) initially present with ocular symptoms, but it is difficult to predict which cases will remain as ocular MG (OMG) or will progress to generalized MG. Herein we evaluated the serologic profile of Japanese OMG and its relationship with clinical features. METHODS: Seventy-three patients with OMG from five Japanese myasthenia gravis (MG) centers were enrolled. Live cell-based assays (CBAs) were used to determine the presence of autoantibodies (Abs) to clustered adult (2α, ß, δ, ε) and fetal (2α, ß, δ, γ) acetylcholine receptor (AChR) isoforms, muscle-specific receptor tyrosine kinase (MuSK), and lipoprotein receptor-related protein-4 (LRP4). RESULTS: Thirty-four of 73 (46.5%) serum samples were positive for Abs against both the adult-type and fetal-type AChR, as expected, but 7 (9.6%) and 2 (2.7%) were positive only for fetal or adult AChR-Abs, respectively. Four (5.4%) samples were positive for MuSK-Abs, but two of these also contained antibodies to fetal AChR or LRP4. Twenty-six (35.6%) samples were seronegative. DISCUSSION: Abs against fetal-specific AChR, MuSK, and LRP4 are found in some patients with OMG. Future studies attempting to predict conversion from ocular symptoms to generalized MG may benefit from measurement of these antibodies.

Very late onset neuromyelitis optica spectrum disorders.

BACKGROUND AND PURPOSE: Neuromyelitis optica spectrum disorder (NMOSD) often presents in the elderly with an insidious onset of symptoms and aggressive progression. There have been anecdotal cases of very late onset (VLO)-NMOSD, but case series reports are rare. The aim of this retrospective study was to clarify the clinical features of VLO-NMOSD. METHODS: According to the age at onset, we classified patients with NMOSD into three subgroups: ≤49 years, early onset NMOSD (EO-NMOSD); 50-69 years, late onset NMOSD (LO-NMOSD); and ≥70 years, VLO-NMOSD. We evaluated the clinical characteristics, magnetic resonance imaging (MRI) findings, laboratory data, and immunotherapies of the groups. RESULTS: Overall, 12 men and 64 women with a median (interquartile range) age at onset and duration of disease of 42.0 (29.0-55.8) years and 70.0 (16.3-143.0) months, respectively, were included. Eight (11%) patients had VLO-NMOSD, 22 (29%) had LO-NMOSD, and 46 (61%) had EO-NMOSD. Patients with EO-NMOSD had a significantly longer interval between episodes as well as time between the first symptom and diagnosis of NMOSD than did those with VLO-NMOSD and LO-NMOSD (p = 0.046). Optic neuritis and nerve lesions on MRI were significantly less frequent in patients with VLO-NMOSD than in those with LO-NMOSD and EO-NMOSD (p = 0.002 and p = 0.028, respectively). In contrast, patients with VLO-NMOSD had higher nadir Expanded Disability Status Scale and Nurick scale scores and a significantly longer spinal lesion length than did those with LO-NMOSD and EO-NMOSD (p = 0.029, p = 0.049, and p = 0.032, respectively). CONCLUSIONS: Patients with VLO-NMOSD tend to develop severe myelitis with long cord lesions but not optic neuritis.

Genomic analysis of multiple myeloma using targeted capture sequencing in the Japanese cohort.

Previous genomic studies have revealed the genomic landscape of myeloma cells. Although some of the genomic abnormalities shown are believed to be correlated to the molecular pathogenesis of multiple myeloma and/or clinical outcome, these correlations are not fully understood. The aim of this study is to elucidate the correlation between genomic abnormalities and clinical characteristics by targeted capture sequencing in the Japanese multiple myeloma cohort. We analysed 154 patients with newly diagnosed multiple myeloma. The analysis revealed that the study cohort consisted of a less frequent hyperdiploid subtype (37·0%) with relatively high frequencies of KRAS mutation (36·4%) and IGH-CCND1 translocation (26·6%) compared with previous reports. Moreover, our targeted capture sequencing strategy was able to detect rare IGH-associated chromosomal translocations, such as IGH-CCND2 and IGH-MAFA. Interestingly, all 10 patients harboured MAX mutations accompanied by 14q23 deletion. The patients with del(17p) exhibited an unfavourable clinical outcome, and the presence of KRAS mutation was associated with shorter survival in patients with multiple myeloma, harbouring IGH-CCND1. Thus, our study provides a detailed landscape of genomic abnormalities, which may have potential clinical application for patients with multiple myeloma.

Clinical significance of tryptophan catabolism in follicular lymphoma.

The enzyme, indoleamine 2,3-dioxygenase 1 (IDO), catabolizes tryptophan (Trp) in the kynurenine (Kyn) pathway, and is important in suppressing antitumor immune responses in the tumor microenvironment. With regard to previously untreated patients with follicular lymphoma (FL), we sought to establish the prognostic significance of Trp catabolism in this disease. Serum Trp and Kyn levels in 110 patients with FL were quantified, and their relationship to different clinical parameters studied. IDO expression in the lymph nodes of affected patients was studied. Study participants included 54 males and 56 females (age range 39-86, median 62 years), showing a 5-year overall survival (OS) rate of 78.5%. Patients with a high Kyn level (5-year OS, 65.0% vs. 81.7%; p = 0.026), high Kyn/Trp ratio (71.1% vs. 81.7%; p = 0.002), and low hemoglobin (Hb) level (<12.0 g/dL; p = 0.001; a component of FL international prognostic indexes) demonstrated a significantly shorter OS. Multivariate analysis included the following 10 variables: age, sex, serum ß2-microglobulin, Hb, longest diameter of the largest involved node, Ann Arbor stage, serum lactate dehydrogenase, histologic grading, B symptoms, and serum Kyn/Trp ratio; a lower Hb level and a high Kyn/Trp ratio (HR, 3.239; 95% CI, 1.296-8.096) led to a significantly inferior OS. In the microenvironment, some CD11c-positive myeloid dendritic cells but not FL tumor cells were found to produce IDO. Overall, measuring levels of serum Kyn and Trp in individual patients with FL contributed to predicting their prognosis.

Immunohistochemistry for identification of CCND1, NSD2, and MAF gene rearrangements in plasma cell myeloma.

The t(11;14)/CCND1-IGH, t(4;14)/NSD2(MMSET)-IGH, and t(14;16)/IGH-MAF gene rearrangements detected by fluorescence in situ hybridization (FISH) are used for risk stratification in patients with multiple myeloma (MM). Compared with conventional FISH techniques using fresh cells, immunohistochemistry (IHC) is much more cost- and time-efficient, and can be readily applied to routinely prepared formalin-fixed, paraffin-embedded (FFPE) materials. In this study, we performed tissue FISH and IHC employing FFPE specimens, and examined the usefulness of IHC as a tool for detecting CCND1, NSD2, and MAF gene rearrangements. CD138 signals were used to identify plasma cells in tissue FISH and IHC analyses. With cohort 1 (n = 70), we performed tissue FISH and subsequently IHC, and determined IHC cut-off points. In this cohort, the sensitivity and specificity for the 3 molecules were ≥.90 and ≥.96, respectively. With cohort 2, using MM cases with an unknown gene status (n = 120), we performed IHC, and the gene status was estimated using the cut-off points determined with cohort 1. The subsequent FISH analysis showed that the sensitivity and specificity for the 3 molecules were ≥.92 and ≥.98, respectively. CCND1, NSD2, and MAF gene rearrangements were estimated accurately by IHC, suggesting that conventional FISH assays can be replaced by IHC.

Clinical Implications of t(11;14) in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation.

Conventional cytogenetic analyses and fluorescent in situ hybridization (FISH) are helpful for stratifying patients with multiple myeloma (MM) into high-risk [t(4;14), t(14;16), and/or del 17p] and standard-risk [t(11;14)] categories. However, the prognosis of patients with MM treated with autologous stem cell transplantation (ASCT) stratified according to these categories remains unclear. This retrospective observational study analyzed 97 patients with MM who received a single, planned ASCT after treatment with 200 mg/m2 melphalan between 2001 and 2011. The patients were grouped according to chromosomal abnormality, including t(11;14) (n = 45), t(4;14) (n = 31), del 17p (n = 10), t(11;14) with del 17p (n = 7), and t(4;14) with del 17p (n = 4). Median overall survival (OS) of the t(11;14) group (64.1 months) was not significantly different from that of the t(4;14) group (not reached), but it was significantly longer than that of the del 17p group (23.0 months; P = .002). G-banding revealed that the median OS of the t(11;14) group with additional chromosomal abnormalities (ACAs) (46.2 months) was significantly shorter than that of the t(11;14) group without ACAs (not reached; P = .005) and the t(4;14) group (not reached; P = .010). These findings highlight the importance of G-banding in patients with t(11;14) MM.

Cyclin-dependent kinase 9 is a novel specific molecular target in adult T-cell leukemia/lymphoma.

Cyclin-dependent kinase 9 (CDK9), a subunit of the positive transcription elongation factor b (P-TEFb) complex, regulates gene transcription elongation by phosphorylating the C-terminal domain (CTD) of RNA polymerase II (RNAPII). The deregulation of CDK9/P-TEFb has important implications for many cancer types. BAY 1143572 is a novel and highly selective CDK9/P-TEFb inhibitor currently being investigated in phase 1 studies. We evaluated the therapeutic potential of BAY 1143572 in adult T-cell leukemia/lymphoma (ATL). As a result of CDK9 inhibition and subsequent inhibition of phosphorylation at serine 2 of the RNAPII CTD, BAY 1143572 decreased c-Myc and Mcl-1 levels in ATL-derived or human T-cell lymphotropic virus type-1 (HTLV-1)-transformed lines and primary ATL cells tested, leading to their growth inhibition and apoptosis. Median inhibitory concentrations for BAY 1143572 in ATL-derived or HTLV-1-transformed lines (n = 8), primary ATL cells (n = 11), and CD4+ cells from healthy volunteers (n = 5) were 0.535, 0.30, and 0.36 µM, respectively. Next, NOG mice were used as recipients of tumor cells from an ATL patient. BAY 1143572-treated ATL-bearing mice (once daily 12.5 mg/kg oral application) demonstrated significantly decreased ATL cell infiltration of the liver and bone marrow, as well as decreased human soluble interleukin-2 receptor levels in serum (reflecting the ATL tumor burden), compared with untreated mice (n = 8 for both). BAY 1143572-treated ATL-bearing mice demonstrated significantly prolonged survival compared with untreated ATL-bearing mice (n = 7 for both). Collectively, this study indicates that BAY 1143572 showed strong potential as a novel treatment of ATL.

[Richter syndrome successfully treated with ibrutinib monotherapy: two case reports].

The Richter syndrome (RS) is defined as a histologically diagnosed diffuse large B-cell lymphoma (DLBCL) or Hodgkin lymphoma (HL) in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma. A standard treatment for RS has not yet been established. Most patients with RS are treated with combination chemotherapy regimens used for de novo DLBCL or HL. Recently, the Bruton's tyrosine kinase inhibitor, ibrutinib (IBR), has shown remarkable efficacy in CLL; however, limited evidence exists regarding its single agent efficacy in RS. We encountered two patients with RS in whom CLL transformed to DLBCL, confirmed by G-banding/spectral karyotyping analysis. Both patients achieved durable responses for 12 and 10 months, with IBR alone. Hemorrhagic cystitis due to adenovirus occurred in one patient at an initial dose of 420 mg/day, but a dose reduction to 280 mg/day made long-term continuation of IBR possible. Interestingly, retreatment with IBR alone achieved disease control again for 5.5 and 2 months, after these patients underwent salvage chemotherapies for aggressive relapse.

Human T-cell lymphotropic/leukemia virus type 1 (HTLV-1) Tax-specific T-cell exhaustion in HTLV-1-infected individuals.

Adult T-cell leukemia/lymphoma (ATL) is caused by Human T-cell lymphotropic/leukemia virus type 1 (HTLV-1), and a higher HTLV-1 provirus load in PBMC is a risk factor for ATL development. Here, we document a significant inverse correlation between the function of HTLV-1 Tax-specific CTL (Tax-CTL), as assessed by ex vivo cytokine production in response to cognate peptide, and the HTLV-1 provirus load in PBMC in both HTLV-1 asymptomatic carriers (AC) (Spearman rank correlation coefficient [Rs] = -0.494, P = .037, n = 18) and ATL patients (Rs = -0.774, P = .001, n = 15). There was also a significant correlation between the HTLV-1 provirus load and the percentage of PD-1-positive Tax-CTL in both HTLV-1 AC (Rs = 0.574, P = .013) and ATL patients (Rs = 0.676, P = .006). Furthermore, the percentage of PD-1-positive Tax-CTL was inversely correlated with their function in HTLV-1 AC (Rs = -0.542, P = .020), and ATL patients (Rs = -0.639, P = .010). These findings indicate that the function of Tax-CTL decreased as their programmed cell death protein 1 (PD-1) levels increased, parallel to the increased HTLV-1 provirus load in PBMC. We propose that functional Tax-CTL are crucial for determining the HTLV-1 provirus load in PBMC, not only in HTLV-1 AC, but also in ATL, and that PD-1 expression levels are reliable markers of Tax-CTL function. Thus, modulating the immunological equilibrium between Tax-CTL and HTLV-1-infected cells to achieve dominance of functional effectors could represent an ideal strategy for controlling HTLV-1-associated disease.

Clinical significance of tryptophan catabolism in Hodgkin lymphoma.

Indoleamine 2,3-dioxygenase 1 (IDO) is an enzyme catabolizing tryptophan (Trp) into the kynurenine (Kyn) pathway. The purpose of the present study was to determine the clinical significance of Trp catabolism in newly diagnosed Hodgkin lymphoma (HL) patients. We quantified serum Trp and Kyn in 52 HL patients, and analyzed their associations with different clinical parameters including serum soluble CD30 concentration. The IDO expression was evaluated in the patients' affected lymph nodes. The cohort comprised 22 male and 30 female patients (age range, 15-81 years; median, 45 years), with a 5-year overall survival (OS) of 88.6%. The OS was significantly shorter for patients with a high Kyn/Trp ratio (OS at 5 years, 60.0% vs 92.2%), for those with stage IV disease, and for those with lymphocytopenia (<600/mm3 and/or <8% white blood cell count). The latter two parameters are components of the international prognostic score for advanced HL. In contrast, there were no significant differences in OS according to age, serum albumin, hemoglobin, sex, white blood cell count, or serum soluble CD30 (≥ or <285.6 ng/mL). Multivariate analysis using the three variables stage, lymphocytopenia, and serum Kyn/Trp ratio showed that only the latter significantly affected OS. Indoleamine 2,3-dioxygenase 1 was produced by macrophages/dendritic cells, but not by HL tumor cells, and IDO levels determined by immunohistochemistry had a significant positive correlation with the serum Kyn/Trp ratio. In conclusion, quantification of serum Kyn and Trp is useful for predicting prognosis of individual HL patients.

Cyclin-dependent kinase 9 as a potential specific molecular target in NK-cell leukemia/lymphoma.

BAY 1143572 is a highly selective inhibitor of cyclin-dependent kinase 9/positive transcription elongation factor b. It has entered phase I clinical studies. Here, we have assessed the utility of BAY 1143572 for treating natural killer (NK) cell leukemias/lymphomas that have a poor prognosis, namely extranodal NK/T-cell lymphoma, nasal type and aggressive NK-cell leukemia, in a preclinical mouse model in vivo as well as in tissue culture models in vitro Seven NK-cell leukemia/lymphoma lines and primary aggressive NK-cell leukemia cells from two individual patients were treated with BAY 1143572 in vitro Primary tumor cells from an aggressive NK-cell leukemia patient were used to establish a xenogeneic murine model for testing BAY 1143572 therapy. Cyclin-dependent kinase 9 inhibition by BAY 1143572 resulted in prevention of phosphorylation at the serine 2 site of the C-terminal domain of RNA polymerase II. This resulted in lower c-Myc and Mcl-1 levels in the cell lines, causing growth inhibition and apoptosis. In aggressive NK-cell leukemia primary tumor cells, exposure to BAY 1143572 in vitro resulted in decreased Mcl-1 protein levels resulting from inhibition of RNA polymerase II C-terminal domain phosphorylation at the serine 2 site. Orally administering BAY 1143572 once per day to aggressive NK-cell leukemia-bearing mice resulted in lower tumor cell infiltration into the bone marrow, liver, and spleen, with less export to the periphery relative to control mice. The treated mice also had a survival advantage over the untreated controls. The specific small molecule targeting agent BAY1143572 has potential for treating NK-cell leukemia/lymphoma.

Clinical evaluation of a novel and highly sensitive immunoassay for anti-hepatitis B core antigen using a fully automated immunochemical analyzer.

AIM: Recently, the measurement of hepatitis B surface antigen and anti-hepatitis B core antigen (HBcAb) and/or anti-hepatitis B surface antigen has been recommended before various therapies to identify patients at risk of hepatitis B virus (HBV) reactivation. However, a recent study reported that HBV reactivation occurred in HBcAb-negative patients, indicating that it is challenging to identify patients with a history of HBV infection using conventional HBcAb reagent. We developed a highly sensitive HBcAb (HBcAb-HS) assay for reducing the risk of HBV reactivation. METHODS: The HBcAb-HS assay is an automated chemiluminescent enzyme immunoassay system, which is suitable for clinical use. The cut-off was set at 0.020 IU/mL from the distribution patterns of HBcAb-negative specimens, and we evaluated the performance of this assay compared with conventional reagents. RESULTS: This new assay showed a 27-81-fold greater sensitivity than conventional HBcAb reagents; the quantified measurement range was from 0.005 IU/mL to 1.500 IU/mL, and it showed excellent quantitative performance and correlated well with two conventional assays, using the HBcAb-positive specimens. Moreover, it showed 100% specificity for the 469 purchased HBcAb-negative specimens. Notably, this newly developed HBcAb-HS assay showed positivity in the preserved specimens before HBV reactivation, for which conventional HBcAb reagents gave negative results, and the HBcAb-HS assay could detect the lower HBcAb levels even after intensive immunosuppressive therapies, including autologous hematopoietic stem cell transplantation. CONCLUSIONS: The clinical efficacy of the newly developed, highly sensitive HBcAb assay would enable the identification of patients at risk of HBV reactivation more accurately.

[Thrombosis in multiple myeloma].

Reportedly, patients with cancer have an increased risk (four- to seven-fold) of developing thrombotic events (TEs) compared with healthy volunteers. Multiple myeloma (MM) is one of the neoplasms that exhibit a high incidence of TEs, and approximately 10% patients with MM develop TEs during their clinical courses. The underlying risk factors of TEs are classified into patient-, disease-, and treatment-related factors. Specific treatment-related risk factors comprise the use of immunomodulatory drugs combined with dexamethasone. As the occurrence of TE in patients hampers the treatment for MM itself, which results in unfavorable outcomes, elucidating TE pathogenesis and adequate prophylaxis for each patient are essential to prevent MM-related TEs.

[Sporadic late-onset nemaline myopathy with monoclonal gammopathy of undetermined significance mimicking POEMS syndrome].

A 40-year-old female presented with a skin rash, hepatosplenomegaly, hypothyroidism, IgG-λ monoclonal gammopathy, slightly elevated serum VEGF levels, and >1-year history of weakness in the posterior cervical muscles. Based on these symptoms and her clinical course, she was suspected of having POEMS syndrome. However, because there was no sign of peripheral neuropathy (PN), the criteria for the diagnosis of POEMS syndrome were not met. Consequently, she continued follow-up and was under close observation as an outpatient. She complained of slowly progressive dyspnea that was identified as type 2 respiratory failure requiring non-invasive positive pressure ventilation. She received systemic chemotherapy, including thalidomide and dexamethasone, as the respiratory failure was predominantly a result of POEMS-associated PN. Although the skin eruptions improved upon treatment, respiratory failure gradually worsened, and she required mechanical ventilation. The patient was suspected of having sporadic late-onset nemaline myopathy with monoclonal gammopathy of undetermined significance (SLONM-MGUS), because of resistant to chemotherapy and second opinion suggestion. A thigh muscle biopsy revealed the presence of nemaline rods and led to the definitive diagnosis of SLONM-MGUS. Unfortunately, she was unable to receive autologous stem cell transplantation, and finally died because of progressive respiratory failure. SLONM-MGUS is an extremely rare disease but should be considered as a critical, monoclonal-protein related condition.

Epigenetic repression of miR-375 is the dominant mechanism for constitutive activation of the PDPK1/RPS6KA3 signalling axis in multiple myeloma.

Cytogenetic/molecular heterogeneity is the hallmark of multiple myeloma (MM). However, we recently showed that the serine/threonine kinase PDPK1 and its substrate RPS6KA3 (also termed RSK2) are universally active in MM, and play pivotal roles in myeloma pathophysiology. In this study, we assessed involvement of aberrant miR-375 repression in PDPK1 overexpression in MM. An analysis of plasma cells from 30 pre-malignant monoclonal gammopathies of undetermined significance and 73 MM patients showed a significant decrease in miR-375 expression in patient-derived plasma cells regardless of the clinical stage, compared to normal plasma cells. Introduction of miR-375 reduced PDPK1 expression in human myeloma cell lines (HMCLs), indicating that miR-375 is the dominant regulator of PDPK1 expression. In addition, miR-375 introduction also downregulated IGF1R and JAK2 in HMCLs. CpG islands in the MIR375 promoter were pathologically hypermethylated in all 8 HMCLs examined and in most of 58 patient-derived myeloma cells. Treatment with SGI-110, a hypomethylating agent, and/or trichostatin A, a histone deacetylase inhibitor, increased miR-375 expression, but repressed PDPK1, IGF1R and JAK2 in HMCLs. Collectively, these results show the universal involvement of overlapping epigenetic dysregulation for abnormal miR-375 repression in MM, which is likely to contribute to myelomagenesis and to subsequent myeloma progression by activating oncogenic signalling pathways.

HTLV-1 bZIP factor-specific CD4 T cell responses in adult T cell leukemia/lymphoma patients after allogeneic hematopoietic stem cell transplantation.

We document human T lymphotropic virus type 1 (HTLV-1) bZIP factor (HBZ)-specific CD4 T cell responses in an adult T cell leukemia/lymphoma (ATL) patient after allogeneic hematopoietic stem cell transplantation (HCT) and identified a novel HLA-DRB1*15:01-restricted HBZ-derived naturally presented minimum epitope sequence, RRRAEKKAADVA (HBZ114-125). This peptide was also presented on HLA-DRB1*15:02, recognized by CD4 T cells. Notably, HBZ-specific CD4 T cell responses were only observed in ATL patients after allogeneic HCT (4 of 9 patients) and not in nontransplanted ATL patients (0 of 10 patients) or in asymptomatic HTLV-1 carriers (0 of 10 carriers). In addition, in one acute-type patient, HBZ-specific CD4 T cell responses were absent in complete remission before HCT, but they became detectable after allogeneic HCT. We surmise that HTLV-1 transmission from mothers to infants through breast milk in early life induces tolerance to HBZ and results in insufficient HBZ-specific T cell responses in HTLV-1 asymptomatic carriers or ATL patients. In contrast, after allogeneic HCT, the reconstituted immune system from donor-derived cells can recognize virus protein HBZ as foreign, and HBZ-specific immune responses are provoked that contribute to the graft-versus-HTLV-1 effect.

Autologous Tax-specific CTL therapy in a primary adult T cell leukemia/lymphoma cell-bearing NOD/Shi-scid, IL-2Rγnull mouse model.

We expanded human T-lymphotropic virus type 1 Tax-specific CTL in vitro from PBMC of three individual adult T cell leukemia/lymphoma (ATL) patients and assessed their therapeutic potential in an in vivo model using NOG mice bearing primary ATL cells from the respective three patients (ATL/NOG). In these mice established with cells from a chronic-type patient, treatment by i.p. injection of autologous Tax-CTL resulted in greater infiltration of CD8-positive T cells into each ATL lesion. This was associated with a significant decrease of ATL cell infiltration into blood, spleen, and liver. Tax-CTL treatment also significantly decreased human soluble IL-2R concentrations in the sera. In another group of ATL/NOG mice, Tax-CTL treatment led to a significant prolongation of survival time. These findings show that Tax-CTL can infiltrate the tumor site, recognize, and kill autologous ATL cells in mice in vivo. In ATL/NOG mice with cells from an acute-type patient, whose postchemotherapeutic remission continued for >18 mo, antitumor efficacy of adoptive Tax-CTL therapy was also observed. However, in ATL/NOG mice from a different acute-type patient, whose ATL relapsed after 6 mo of remission, no efficacy was observed. Thus, although the therapeutic effects were different for different ATL patients, to the best of our knowledge, this is the first report that adoptive therapy with Ag-specific CTL expanded from a cancer patient confers antitumor effects, leading to significant survival benefit for autologous primary cancer cell-bearing mice in vivo. The present study contributes to research on adoptive CTL therapy, which should be applicable to several types of cancer.