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Molecular polymerase chain reaction diagnosis of pulmonary mucormycosis caused by Cunninghamella bertholletiae KOBAYASHI M, TOGITANI K, MACHIDA H, UEMURA Y, OHTSUKI Y, TAGUCHI H. Respirology 2004; 9: 397–401 Mucormycosis is an uncommon but frequently fatal infection caused by strains of mucorales in immunocompromised hosts. In this study, we report a case of pulmonary mucormycosis associated with acute lymphocytic leukaemia caused by Cunninghamella bertholletiae, a rare pathogen. Retrospective analysis of the stored serum, sputum, and necropsy lung tissue samples from this patient, enabled subspecies identification by means of panfungal polymerase chain reaction (PCR), direct DNA sequencing of the PCR products, and homology search with nucleotide basic local alignment search tool. The development of a reliable diagnostic blood test for angio-invasive fungal infections such as mucormycosis is desirable, because the sensitivity of culture for these fungi is extremely low. Panfungal PCR on serial serum samples might be useful for the diagnosis of pulmonary mucormycosis. [ABSTRACT FROM AUTHOR]

Megaloblastic anemia (MBA) is a reversible metabolic disorder that responds well to vitamin B12 supplementation. It contrasts with myelodysplastic syndrome (MDS), an irreversible neoplastic condition characterized by hematopoietic stem cell abnormalities. To date, no association has been identified between these two distinct etiologies, and they are considered independent diseases. However, despite their distinct classifications, both conditions present macrocytic anemia, similar bone marrow findings, and sometimes have common chromosomal abnormalities, which can lead to occasional misdiagnoses. Herein, we present a patient initially diagnosed with pernicious anemia (PA) who showed improvement with replacement therapy but subsequently became resistant to treatment and eventually developed MDS. Quantitative assessment of Wilm's tumor-1 (WT1) mRNA has emerged as a valuable tool for gauging MDS disease status and distinguishing it from related disorders, such as aplastic anemia. In our investigation of 30 patients with MBA, we explored WT1 mRNA expression. We observed its presence in 10 patients with PA, which suggests a potential link between PA and hematopoietic tumors., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Institutional Ethics Committee of Chikamori Hospital issued approval 323. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Uemura et al.)

Tocilizumab has been used to treat idiopathic multicentric Castleman disease (iMCD). As tocilizumab prevents interleukin-6 from exerting pro-inflammatory effects, there is some concern about a delayed diagnosis of severe infections during tocilizumab treatment. Although serious infections during tocilizumab therapy have been previously described in patients with rheumatoid arthritis, they have not been reported in iMCD. We herein report a case of disseminated Staphylococcus aureus infection after a superficial skin wound followed by psoas and mediastinal abscesses with pyogenic spondylodiscitis in an iMCD patient with diabetes. Physicians should be alert for the occurrence of disseminated S. aureus infection after even minor skin injury during tocilizumab therapy.

A 52-year-old man presented with palatine tonsillar swelling caused by follicular lymphoma. His tumor burden was low, but exacerbation of snoring and dysphagia was observed. Considering the first wave of coronavirus disease 2019 (COVID-19) pandemic, he received palliative 4-Gy irradiation to the tonsils in 2 fractions, which induced partial regression of tonsillar swellings and eradication of the circulating lymphoma cells. We suggest that low-dose radiotherapy triggered an abscopal effect of lymphoma, which allowed the patient time to receive COVID-19 vaccination before starting immunosuppressive chemo-immunotherapy.

We report a case of mantle cell lymphoma mimicking Castleman disease. A 76-year-old man presented with generalized lymphadenopathy, splenomegaly, anemia, polyclonal gammopathy, and pulmonary infiltrations. Lymph node biopsy revealed histological features of hyaline vascular Castleman disease. Treatment with prednisolone induced lymphocytosis with immunophenotypic and genetic features of mantle cell lymphoma. A detailed immunohistochemical study of the lymph node demonstrated a mantle cell lymphoma-mantle zone growth pattern. Glucocorticoid-induced distribution lymphocytosis has not been reported in mantle cell lymphoma. Careful observation of circulating lymphocytes during steroid treatment may enable diagnosis of the underlying occult lymphoma in a subset of patients exhibiting clinical manifestations of Castleman disease.

We report a case of early asymptomatic acute promyelocytic leukemia (APL) with leukopenia as the only hematologic abnormality. A 55-year-old woman was referred to our hospital with leukopenia (white blood cell [WBC] count of 1,500/µl with 36% neutrophils), which was incidentally determined during an annual medical checkup. Two months before the presentation, her WBC was 3,400/µl with 60% neutrophils. A WBC count was 1,200/µl with 40% neutrophils. Immature myeloid cells were not observed. Her hemoglobin level and platelet count were normal. Moreover, no clinical or laboratory evidence was suggestive of disseminated intravascular coagulation or infection. The peripheral blood WT1 mRNA level was increased to 26,000 copies/µg RNA. The bone marrow aspirate smear revealed 40% myeloperoxidase-positive promyelocytes with occasional Auer rods and faggots; however, circulating leukemia cells were not revealed by cell morphology or flow cytometry analysis. Quantitative reverse-transcription polymerase chain reaction analysis revealed WT1 and PML-RARA fusion transcripts in both the peripheral blood and bone marrow samples. Thus, the determination of peripheral blood WT1 expression may be sufficiently sensitive for detecting a small number of circulating APL cells.

We report a case of pseudo-prolongation of activated partial thromboplastin time (APTT), which was suspected to be caused by an animal-derived phospholipid. A 78-year-old woman was referred to our hospital because of an unexplained APTT prolongation. She had compensated alcoholic liver cirrhosis, with modestly decreased platelet count and normal prothrombin time, and no bleeding tendency. The APTT was 66 seconds in a test using phospholipid extracted from rabbit brain but was 34.9 seconds with synthetic phospholipids. The artifactual pseudo-prolongation of the APTT was seemingly attributable to the susceptibility of the test reagents to low factor XII levels. Thus, tests with different APTT reagents would be useful to physicians in the diagnosis of similar cases.

We report the case of a patient with lead poisoning caused by a dietary supplement. A 40-year-old man was referred to us due to intermittent upper abdominal pain and normocytic anemia. His hemoglobin level was 9.3 g/dl, with basophilic stippling in 2.8% of red blood cells. Bone marrow aspirate smear showed ringed sideroblasts that represented 19% of the erythroblasts. The patient reported the use of an unauthorized, Indian-manufactured dietary supplement and was diagnosed with lead poisoning based on a significantly high blood lead level. The dietary supplement was discontinued, and he was successfully treated with lead chelation therapy, and his hemoglobin level normalized within 2 months.

Acquired hypofibrinogenemia is observed in patients with severe liver disease, disseminated intravascular coagulation, and high-volume perioperative fluid replacement. In lymphoblastic leukemia, hypofibrinogenemia is most frequently caused by the administration of L-asparaginase. Here we report the cases of two patients with acquired hypofibrinogenemia that occurred during steroid-containing chemotherapy treatment against lymphoblastic blast crisis of chronic myeloid leukemia in the first case and acute lymphoblastic leukemia in the second case. Administration of steroids repeatedly and promptly caused hypofibrinogenemia, irrespective of the products (prednisolone, dexamethasone, or methylprednisolone) or routes (oral or intravenous) that were used. Monitoring of the fibrinogen levels, especially during the first course of steroid therapy, would be useful for early diagnosis.

We report the case of a 26-year-old male patient with chronic myelogenous leukemia in the chronic phase with the e13a3 (b2a3) variant of BCR-ABL1 fusion. Despite the presence of Philadelphia chromosome and fluorescence in situ hybridization-detectable BCR-ABL1 fusion signals, quantitative measurement of BCR-ABL1 on the ABL1 using a reverse primer in exon 2 of ABL1 failed to detect the fusion transcripts. PCR direct sequencing analysis with a sense primer for exon 13 of BCR and an antisense primer for exon 3 of ABL1 revealed the e13a3 variant of BCR-ABL1 fusion. The variant fusion transcript level was successfully monitored by the TaqMan assay using a forward primer and probe both in exon 13 of BCR and a reverse primer in exon 3 of ABL1. The patient responded extremely well to imatinib treatment, similar to previously reported e13a3 cases. The patient achieved a molecular response (undetectable e13a3 transcripts) after 12 months of treatment.

We conducted a multicenter study on anti-programmed cell death-1 monoclonal antibodies (anti-PD-1 mAbs) before/after allogeneic hematopoietic cell transplantation (allo-HCT) for Hodgkin lymphoma. Anti-PD-1 mAbs were administered to 25 patients before allo-HCT and to 20 after allo-HCT. In pre-allo-HCT setting, the median interval from the last administration to allo-HCT was 59 days. After allo-HCT, 12 patients developed non-infectious febrile syndrome requiring high-dose corticosteroid. The cumulative incidences of grade II-IV acute graft-versus-host disease (aGvHD) were 47.1%. Eight patients who had GvHD prophylaxis with post-transplant cyclophosphamide (PTCy) had less frequent aGvHD (grade II-IV, 14.6% versus 58.8%; P = 0.086). The 1 year overall survival (OS), relapse/progression, and non-relapse mortality rates were 81.3%, 27.9%, and 8.4%. In post-allo-HCT setting, the median interval from allo-HCT to the first administration was 589 days. The overall and complete response rates were 75% and 40%. At 100 days after anti-PD-1 therapy, the cumulative incidences of grade II-IV aGvHD, moderate-to-severe chronic GvHD, and grade 3-4 immune-related toxicity were 15.0%, 30.0%, and 30.0%. While the 1 year relapse/progression rate was 47.4%, the 1 year OS probability was 89.7%. In conclusion, immune-related complications were frequent despite modifications of GvHD prophylaxis or anti-PD-1 mAb dosing. In anti-PD-1-mAb-pretreated patients, PTCy-based GvHD prophylaxis may be effective.

The prognostic impact of KIT mutation on core-binding factor acute myeloid leukemia (CBF-AML) remains controversial. We registered 199 newly diagnosed de novo CBF-AML patients, aged 16 to 64 years, who achieved complete remission. They received 3 courses of high-dose cytarabine therapy and no further treatment until hematological relapse. Mutations in exons 8, 10-11, and 17 of the KIT gene were analyzed. Furthermore, we analyzed mutations in 56 genes that are frequently identified in myeloid malignancies and evaluated minimal residual disease (MRD). The primary end point was relapse-free survival (RFS) according to KIT mutations. The RFS in KIT-mutated patients was inferior to that in unmutated patients (hazard ratio, 1.92; 95% confidence interval, 1.23-3.00; P = .003). Based on subgroup analysis, KIT mutations had a prognostic impact in patients with RUNX1-RUNX1T1, but not in those with CBFB-MYH11, and only exon 17 mutation had a significant prognostic impact. Multivariate Cox regression analysis with stepwise selection revealed that the KIT exon 17 mutation and the presence of extramedullary tumors in patients with RUNX1-RUNX1T1, and loss of chromosome X or Y and NRAS mutation in patients with CBFB-MYH11 were poor prognostic factors for RFS. MRD was evaluated in 112 patients, and it was associated with a poorer RFS in the patients with CBFB-MYH11, but not in those with RUNX1-RUNX1T1. These results suggested that it is necessary to separately evaluate AML with RUNX1-RUNX1T1 or CBFB-MYH11 according to appropriate prognostic factors. This study was registered at www.umin.ac.jp/ctr/ as #UMIN000003434., (© 2020 by The American Society of Hematology.)

Objective Little information is available about the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) for patients with secondary myelofibrosis from essential thrombocythemia (ET) and polycythemia vera (PV). A nationwide retrospective study of the outcome of HSCT for post-ET and post-PV myelofibrosis was conducted in Japan. Patients and Methods Clinical data for patients with post-ET (n=29) and post-PV (n=9) myelofibrosis who had received first allogeneic HSCT were extracted from the Transplant Registry Unified Management Program, which is a registry of the outcomes of HSCT in Japan. Results Five patients died without neutrophil recovery within 60 days after transplantation. The incidence of neutrophil recovery was significantly lower in umbilical cord blood (UCB) transplantation than in related donor transplantation (40% vs. 92%, p=0.010). The 1-year non-relapse mortality for post-ET and post-PV myelofibrosis was 35% and 27%, respectively (p=0.972). No patient or transplantation characteristics were associated with non-relapse mortality. The 4-year overall survival for post-ET and post-PV myelofibrosis was 46% and 65%, respectively (p=0.362). A univariate analysis identified UCB transplantation (vs. related donor, p=0.017) and ≥10 times red blood cell transfusions before transplantation (vs. <10 times, p=0.037) as predictive of a lower overall survival. Conclusion Allogeneic HSCT provides a long-term survival for at least some patients with post-ET and post-PV myelofibrosis. Further studies with more patients are required to determine the best alternative donor.

TAFRO syndrome is a systemic inflammatory disorder that is characterized by thrombocytopenia, anasarca, myelofibrosis, renal dysfunction, and organomegaly. Although thrombocytopenia is one of the major features of TAFRO syndrome, complications of disseminated intravascular coagulation (DIC) are not common. The therapeutic strategy for TAFRO syndrome complicated by DIC has not been established. We herein describe a case of TAFRO syndrome with DIC that was successfully treated with tocilizumab (an anti-IL-6 receptor antibody) and recombinant thrombomodulin (rTM). This case suggests a possible therapeutic benefit of rTM in patients with TAFRO syndrome complicated by DIC.

The objective of this prospective clinical trial (JALSG-STIM213, UMIN000011971) was to evaluate treatment-free remission (TFR) rates after discontinuation of imatinib in chronic myeloid leukemia (CML). CML patients who received imatinib treatment for at least 3 years and sustained deep molecular response for at least 2 years were eligible. Molecular recurrence was defined as loss of major molecular response (MMR). Of the 68 eligible patients, 38.2% were women, the median age was 55.0 years, and the median duration of imatinib treatment was 97.5 months. The 12-month TFR rate was 67.6%. Patients who lost MMR were immediately treated with imatinib again; all re-achieved MMR. Three-year treatment-free survival (TFS) was estimated as 64.6% using the Kaplan-Meier method. Undetectable molecular residual disease (UMRD) was defined as no BCR-ABL1 in > 100,000 ABL1 control genes using international scale polymerase chain reaction. UMRD at the study baseline was found to be predictive of continuation of TFR. Our findings suggest that CML patients who meet all the eligibility criteria that have commonly been used in the TFR trials are able to discontinue imatinib use safely. TFR may thus be valuable as a new goal for CML treatment in Japan.

A 20-year-old woman had a fever, pancytopenia, and liver failure, and was suspected to be suffering from chronic active Epstein-Barr virus (EBV) infection, based on the detection of high EBV-DNA and EBV antibody titers at another hospital. At our institution one month later, clinical manifestations had diminished, and antibody titers had decreased but remained elevated relative to normal levels. Four days later, the patient required hospitalization due to fever, liver damage, and cervical lymphadenopathy. Bone marrow examination and lymph node biopsy results showed EBV-positive cytotoxic T-cells that were predominantly CD4-positive. The disease followed a fulminant course and the patient died of multiple organ failure on hospitalization day 11. Because complicated chromosomal aberrations and T-cell receptor gene rearrangements were identified, we diagnosed her as having systemic EBV-positive T-cell lymphoproliferative disorder of childhood. This disease type includes a lymphoproliferative disorder that is associated with chronic active EBV infection. However, it is clinically different from the type following acute EBV infection. We consider distinguishing between these two types to be important for selecting an early diagnostic procedure and the optimal therapy.

Background: Synchronous primary gastric adenocarcinoma and lymphoma is a rare occurrence. The aim of the present retrospective study was to analyze the clinicopathological characteristics and therapeutic outcomes of patients with this rare condition to identify post-therapeutic prognostic factors., Patients and Methods: A PubMed and MEDLINE search was performed to identify relevant articles, using the keywords 'gastric cancer' and 'gastric malignant lymphoma', while additional articles were obtained from references within these papers. A total of 57 patients who were treated for synchronous primary gastric adenocarcinoma and lymphoma were included in the study. A retrospective review was performed on the clinical characteristics of this disease., Results: The median survival time for patients in this study was 81 months and the overall 1- and 5-year survival rates after therapy were 77.6% and 69.0%, respectively. The median survival period of patients with an advanced gastric cancer was significantly shorter than for early gastric cancer (p<0.001), while the depth of gastric lymphoma invasion did not significantly affect survival time. The median survival period of patients who underwent total gastrectomy was significantly shorter than that of those who underwent distal gastrectomy (p=0.035). Gastric lymphomas were significantly larger than the gastric adenocarcinomas (6.0 vs. 2.7 cm, respectively; p=0.012)., Conclusion: The prognosis for synchronous gastric adenocarcinoma and lymphoma might depend more on the behavior of the adenocarcinoma than on the lymphoma, in which case the treatment and therapeutic outcomes could depend on the adenocarcinoma status., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

We herein report a rare case of paroxysmal nocturnal hemoglobinuria (PNH) who repeatedly developed coronary arterial thromboembolism. Anticoagulant therapies including heparin, aspirin as an antiplatelet agent and even drug-eluting stent placement in the coronary artery failed to prevent the recurrence of ischemic heart disease. Of note, initiating the administration of a humanized anti-C5 antibody, eculizumab, achieved prompt thrombolysis and maintenance treatment with eculizumab prevented the recurrence of thromboembolic disease in this patient. Taking these observations together, we suggest that the use of eculizumab be considered for treatment or prevention of arterial thrombosis complicated by PNH, although arterial thrombosis is an extremely rare event in the Japanese population.

From 2001 to 2012, 71 individuals with hematological diseases received HSCT in our institution. Of these, 41 developed disseminated intravascular coagulation (DIC) in association with various underlying conditions. The patients who developed DIC after 2008 (n = 23) were treated by recombinant human soluble thrombomodulin (rTM), and the others (n = 11) were treated by either heparin and/or antithrombin III concentrate. Seven patients did not receive any anticoagulant therapy. Of note, treatment for coagulopathy by rTM significantly improved clinical outcomes of patients at day 100 and dramatically prolonged their overall survival (P = 0.044). Taken together, rTM is useful to improve clinical outcomes of transplant recipients with coagulopathy., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We treated individuals for disseminated intravascular coagulation (DIC) caused by acute promyelocytic leukemia (APL) (n=9) using human soluble thrombomodulin (rTM) in combination with all-trans retinoic acid (ATRA) and chemotherapy, and compared the clinical outcomes with historical control patients (n=8) treated with ATRA and/or chemotherapy. Two control patients developed intracranial vascular incidents. On the other hand, no bleeding related mortality was noted in rTM-treated patients. Notably, treatment with rTM rescued patients from DIC earlier than historical controls (log rank test, p=0.019). These results suggest that administration of rTM should be considered for the treatment of individuals with DIC associated with APL., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

We conducted a retrospective analysis to evaluate the impact on clinical outcomes of adding rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) treatment for diffuse large B-cell lymphoma (DLBCL) patients in Japan. A propensity score method was used to compensate for the non-randomized study design. From January 2000 to December 2004, 378 patients who were newly diagnosed with DLBCL at 13 institutes were enrolled: 123 in the rituximab plus CHOP-based chemotherapy (R+) group, and 255 in the CHOP-based chemotherapy only (R-) group. The complete response rate was significantly higher in the R+ group than in the R- group (77.7 vs. 69.4%, P < 0.001). The progression-free survival (PFS) at 2 years was 62.4% in the R+ group and 57.0% in the R- group. The 2-year overall survival (OS) was 76.9% for the R+ group and 70.5% for the R- group. A multivariate analysis revealed that the addition of rituximab was a strong independent prognostic factor for PFS (hazard ratio 0.64, 95% CI 0.43-0.96, P = 0.031). A subgroup analysis revealed that R+ particularly benefited younger patients (hazard ratio 0.25, 95% CI 0.08-0.75, P = 0.013). IPI also showed significant impact for PFS (hazard ratio 1.82, 95% CI 1.55-2.14 for one score increase, P < 0.001) as well as OS (hazard ratio 2.10, 95% CI 1.71-2.57, P < 0.001). In summary, the addition of rituximab to CHOP-based chemotherapy results in better outcomes for Japanese DLBCL patients, particularly younger patients.

The FMS-like tyrosine kinase 3 (FLT3) is a cell surface receptor tyrosine kinase. Activating mutations of this gene occur in nearly 30% of acute myelogenous leukemia (AML) patients. These mutations, in part, result in activation of mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathways. In this study, we found that AZD6244 (ARRY-142886), a novel inhibitor of MEK1/2 kinases, effectively inhibited the proliferation of acute biphenotypic leukemia MV4-11 and acute monocytic leukemia MOLM13 cells. The concentrations that inhibited 50% growth were approximately 0.3 and 1.2 microM, respectively, as measured by thymidine uptake on day 2 of culture. AZD6244 potently down-regulated the levels of phospho-ERK1/2 and its downstream effector, p-p70S6K, in the MV4-11 and MOLM13 cells as measured by Western blot analysis. Interestingly, when AZD6244 was combined with sunitinib, a FLT3 kinase inhibitor, growth inhibition and apoptosis of both MV4-11 and MOLM13 cells were synergistically enhanced in association with further down-regulation of phospho-ERK1/2 and p-p70S6K in these cells. Taken together, concomitant blockade of FLT3 and MEK signaling represents a promising treatment strategy for individuals with leukemia who possess activating mutations of FLT3.

Ki11502 is a novel multitargeted receptor tyrosine kinase (RTK) inhibitor with selectivity against platelet-derived growth factor receptor alpha/beta (PDGFRalpha/beta). Ki11502 (0.1-1 nM, 2 days) profoundly caused growth arrest, G(0)/G(1) cell-cycle arrest, and apoptosis associated with down-regulation of Bcl-2 family proteins in the eosinophilic leukemia EOL-1 cells having the activated FIP1-like 1/PDGFRalpha fusion gene. Ki11502 decreased levels of p-PDGFRalpha and its downstream signals, including p-Akt, p-ERK, and p-STAT5, in EOL-1 cells. Of note, Ki11502 was also active against imatinib-resistant PDGFRalphaT674I mutant. In addition, Ki11502 inhibited proliferation of biphenotipic leukemia MV4-11 and acute myelogenous leukemia MOLM13 and freshly isolated leukemia cells having activating mutations in FMS-like tyrosine kinase 3 (FLT3). This occurred in parallel with the drug inhibiting FLT3 and its downstream signal pathways, as measured by fluorescence-activated cell sorting using the phospho-specific antibodies. In addition, Ki11502 totally inhibited proliferation of EOL-1 cells growing as tumor xenografts in SCID mice without any noticeable adverse effects. Taken together, Ki11502 has profound antiproliferative effects on select subsets of leukemia including those possessing imatinib-resistant mutation.

Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive disease with a poor prognosis in which nuclear factor kappa B (NF-kappaB) is thought to play a role. This study explored the effects of histone deacetylase inhibitors (HDACIs) MS-275, suberoylanilide hydroxamic acid (SAHA), and LBH589 on both human T-cell lymphotropic virus type I (HTLV-1)-infected T cells (MT-1, -2, -4, and HUT102) and freshly isolated ATL cells harvested from patients. HDACIs effectively inhibited the proliferation of these cells. For example, MS-275, SAHA, and LBH589 effectively inhibited the proliferation of MT-1 cells with ED(50s) of 6microM, 2.5microM, and 100nM, respectively, as measured by 3-(4,5-dimethylithiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay on day 2 of culture. In addition, HDACIs induced cell cycle arrest at the G2/M phase and apoptosis of HTLV-1-infected T-cells in conjunction with regulation of apoptosis-related proteins. Electrophoretic mobility shift assay showed that exposure of HTLV-1-infected T-cells to HDACIs for 48h inhibited formation of the NF-kappaB/DNA binding complex. Moreover, we found that HDACIs accumulated NF-kappaB and inhibitory subunit of NF-kappaB in the cytoplasm in conjunction with the down-regulation of NF-kappaB in the nucleus, suggesting that HDACIs blocked nuclear translocation of NF-kappaB. Based on these findings, we believe HDACIs can be useful for treating patients with ATL or other types of cancer in which NF-kappaB plays a role.

Aurora kinases play an important role in chromosome alignment, segregation, and cytokinesis during mitosis. We have recently shown that hematopoietic malignant cells including those from acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) aberrantly expressed Aurora A and B kinases, and ZM447439, a potent inhibitor of Aurora kinases, effectively induced growth arrest and apoptosis of a variety of leukemia cells. The present study explored the effect of AZD1152, a highly selective inhibitor of Aurora B kinase, on various types of human leukemia cells. AZD1152 inhibited the proliferation of AML lines (HL-60, NB4, MOLM13), ALL line (PALL-2), biphenotypic leukemia (MV4-11), acute eosinophilic leukemia (EOL-1), and the blast crisis of chronic myeloid leukemia K562 cells with an IC50 ranging from 3 nM to 40 nM, as measured by thymidine uptake on day 2 of culture. These cells had 4N/8N DNA content followed by apoptosis, as measured by cell-cycle analysis and annexin V staining, respectively. Of note, AZD1152 synergistically enhanced the antiproliferative activity of vincristine, a tubulin depolymerizing agent, and daunorubicin, a topoisomerase II inhibitor, against the MOLM13 and PALL-2 cells in vitro. Furthermore, AZD1152 potentiated the action of vincristine and daunorubicin in a MOLM13 murine xenograft model. Taken together, AZD1152 is a promising new agent for treatment of individuals with leukemia. The combined administration of AZD1152 and conventional chemotherapeutic agent to patients with leukemia warrants further investigation.