Tγδ LGLL identifies a subset with more symptomatic disease: analysis of an international cohort of 137 patients.

Tγδ large granular lymphocyte leukemia (LGLL) is a rare variant of T-cell LGLL (T-LGLL) that has been less investigated as compared with the more frequent Tαß LGLL, particularly in terms of frequency of STAT3 and STAT5b mutations. In this study, we characterized the clinical and biological features of 137 patients affected by Tγδ LGLL; data were retrospectively collected from 1997 to 2020 at 8 referral centers. Neutropenia and anemia were the most relevant clinical features, being present in 54.2% and 49.6% of cases, respectively, including severe neutropenia and anemia in ∼20% of cases each. Among the various treatments, cyclosporine A was shown to provide the best response rates. DNA samples of 97 and 94 cases were available for STAT3 and STAT5b mutation analysis, with 38.1% and 4.2% of cases being mutated, respectively. Clinical and biological features of our series of Tγδ cases were also compared with a recently published Tαß cohort including 129 cases. Though no differences in STAT3 and STAT5b mutational frequency were found, Tγδ cases more frequently presented with neutropenia (P = .0161), anemia (P < .0001), severe anemia (P = .0065), and thrombocytopenia (P = .0187). Moreover, Vδ2- cases displayed higher frequency of symptomatic disease. Overall, Tγδ cases displayed reduced survival with respect to Tαß cases (P = .0017). Although there was no difference in STAT3 mutation frequency, our results showed that Tγδ LGLL represents a subset of T-LGLL characterized by more frequent symptoms and reduced survival as compared with Tαß LGLL.

[Aplastic anemia following drug-induced liver injury].

Aplastic anemia (AA), a hematopoietic disorder characterized by hypocellular bone marrow, is caused by immunologically-mediated hematopoietic stem cell injury. Viral infection is hypothesized as the underlying cause of hepatitis-associated AA, although its mechanism is still unclear. This report describes a case of AA following suspected drug-induced liver injury (DILI). An 18-year-old man developed severe liver dysfunction after taking oral over-the-counter drugs. The patient was diagnosed with suspected DILI based on drug-induced lymphocyte stimulation test and liver biopsy results. Although liver dysfunction improved after a course of steroid pulse therapy and liver supporting therapy, the man gradually developed pancytopenia within 3 months of DILI diagnosis, prompting the diagnosis of AA following DILI. Paroxysmal nocturnal hemoglobinuria-type cells were detected by high-sensitivity flow cytometry. Immunosuppressive therapy with antithymocyte globulin and cyclosporin was administered, with pancytopenia improvement. To the best of our knowledge, this is the first report in the literature with a case of AA following DILI, and we believe it is important for evaluating the pathogenesis of drug-induced and hepatitis-associated AA.

[Recurrent invasive pneumococcal disease in a patient with IgG-κ smoldering multiple myeloma].

A 68-year-old female with smoldering multiple myeloma (IgG-κ type) was admitted to the hospital owing to general fatigue, fever, and pain in the right leg. On the day following admission, she developed shock, and a blood culture revealed Streptococcus pneumoniae. She was diagnosed with septic shock and invasive pneumococcal disease (IPD). She received antibiotics and intravenous immunoglobulin and improved after several days. She had a history of recurrent IPD and had received the pneumococcal polysaccharide vaccine 23 (PPSV23) 2 years earlier. Therefore, we inquired with the National Institute of Infectious Diseases if the pneumococcal serotype isolated from her present IPD contained PPSV23. The results showed that her serotype was 19F, a serotype present in PPSV23. We administered pneumococcal conjugate vaccine 13 (PCV13) ; however, she was unable to mount high enough opsonophagocytic assay titers against some serotypes, including 19F. We think she was unable to mount effective humoral immune responses to PPSV23 or PCV13 owing to her underlying disease, smoldering myeloma. It should be considered how IPD can be effectively prevented in patients with multiple myeloma.

[Splenic diffuse red pulp small B-cell lymphoma diagnosed by splenectomy initially mimicking hairy cell leukemia-Japanese variant].

A 62-year-old man presented to the hospital with thrombocytopenia, and splenomegaly was detected. His blood films prepared by natural air drying revealed medium-sized lymphocytes with unevenly distributed large and small villous projections. The cytoplasm was basophilic, nuclei were oval with clumped chromatin, and nucleoli were absent in most cells. Immune phenotypes CD19+, CD20+, CD11c+, FMC7+, IgM+, and Igκ+ were detected. TRAP stain appeared negative, IgH JH chain genes were monoclonally rearranged, and BRAF V600E mutation was not detected. On the basis of these findings, hairy cell leukemia-Japanese variant (HCL-JV) was strongly suspected. The patient was followed up for >4 years without treatment. However, because thrombocytopenia and splenomegaly gradually progressed, splenectomy was performed. Microscopic examination confirmed that the splenic white pulp was atrophic. Moreover, infiltrates comprising small-to-medium-sized atypical lymphocytes with inconspicuous nucleoli were predominantly detected in the congested red pulp. On the basis of these results and immune histochemical findings, the patient was diagnosed with splenic diffuse red pulp small B-cell lymphoma (SDRPL). Here we discussed whether the aforementioned diseases (HCL-JV and SDRPL) are the same; however, further accumulation of cases is essential to draw a definite conclusion.

Long-term outcome of patients with acquired chronic pure red cell aplasia (PRCA) following immunosuppressive therapy: a final report of the nationwide cohort study in 2004/2006 by the Japan PRCA collaborative study group.

Immunosuppressive therapy has been employed as the initial treatment for acquired chronic pure red cell aplasia (PRCA), such as idiopathic, thymoma-associated, or large granular lymphocyte (LGL) leukaemia-associated PRCA, which is thought to be immune-mediated. To explore the overall long-term outcome following immunosuppression and to identify the risk factors for death in these disorders, we conducted nationwide surveys in Japan 2004 and 2006, and identified a total of 185 patients with acquired chronic PRCA, including 72 idiopathic, 41 thymoma-associated and 14 LGL leukaemia-associated cases of PRCA for whom data was available. The present study evaluated 127 patients with these three subsets of PRCA. The median overall survival has not yet been reached in idiopathic PRCA. The estimated median overall survival times in patients with thymoma-associated and LGL leukaemia-associated PRCA were 142·1 and 147·8 months, respectively. Twenty-two deaths were reported, and the response to induction therapy and relapse of anaemia were found to be associated with death. The major causes of death were infection in seven patients and organ failure in another seven patients. The results suggest that maintenance therapy and the management of infectious complications are crucial for improving the prognosis of chronic PRCA.

Prognostic biomarkers in patients with localized natural killer/T-cell lymphoma treated with concurrent chemoradiotherapy.

Concurrent chemoradiotherapy has become one of the standard management approaches for newly diagnosed localized nasal natural killer (NK)/T-cell lymphoma (NKTCL). Few data are available on the prognostic biomarkers of NKTCL among patients treated with concurrent chemoradiotherapy. To evaluate the prognostic significance of immunophenotypic biomarkers for patients treated with concurrent chemoradiotherapy, latent membrane protein 1 (LMP1), cutaneous lymphocyte antigen (CLA) and cell origin were examined in samples from 32 patients who were enrolled in the Japan Clinical Oncology Group 0211 trial and treated with concurrent chemoradiotherapy. LMP1 and CLA were positive in 66% (19/29) and 29% (9/31) of the cases examined, respectively. The median follow-up duration was 68 months (range, 61-94). The patients with LMP1-positive tumors showed a better overall survival (OS) than the patients with LMP1-negative tumors (hazard ratio, 0.240; 95% confidence interval [CI], 0.057-1.013; 80% CI, 0.093-0.615; P = 0.035). All five patients with LMP1-negative tumors who experienced disease progression died of lymphoma, and both patients with local failure had LMP1-negative tumors. There was no significant difference in OS according to CLA expression. A total of 27 (84%) cases were of NK-cell origin, two were of αß T-cell origin and three were of γδ T-cell origin. In contrast to those with tumors of NK-cell origin, all five patients with NKTCL of T-cell origin were alive without relapse at the last follow up. Our results indicate that LMP1 expression is a favorable prognostic marker and suggest that a T-cell origin of the tumor may be a favorable prognostic marker for patients with localized NKTCL treated with concurrent chemoradiotherapy.

Prospective measurement of Epstein-Barr virus-DNA in plasma and peripheral blood mononuclear cells of extranodal NK/T-cell lymphoma, nasal type.

Epstein-Barr virus (EBV)-DNA was prospectively analyzed in plasma and mononuclear cells (MNCs) from peripheral blood in patients with extranodal natural killer (NK)/T-cell lymphoma, nasal type, to evaluate the clinical significance for diagnosis, monitoring the tumor burden, and prognostication. Thirty-three patients were enrolled, and 32 were evaluable. Pretreatment plasma and MNC EBV-DNA was detectable in 14 (range, 50-71 000 copies/mL) and 6 patients (range, 20-780 copies/µg DNA), respectively, and both were well correlated (r = 0.8741, P < .0001). Detectable plasma EBV-DNA was associated with higher clinical stage (P = .02), presence of B symptoms (P = .02), worse performance status (P = .02), and higher serum soluble IL-2 receptor level (P < .0001). Twenty-two patients attained complete response. Plasma EBV-DNA level was significantly higher in nonresponders than in responders (mean, 16,472 vs 2,645 copies/mL; P = .02). Multivariate analysis showed clinical stage (hazard ratio, 9.0; 95% confidence interval, 1.8%-45.0%) and pretreatment plasma EBV-DNA (hazard ratio, 10.6; 95% confidence interval, 1.3%-87.0%) were significant prognostic factors. Three-year overall survival of plasma EBV-DNA positive and negative patients was 42.9% and 94.4%, respectively (P = .0009). Plasma was a preferable sample for this purpose in NK/T-cell lymphoma, nasal type, and EBV-DNA level was a good indicator for response and overall survival.

Aggressive natural killer cell leukemia: therapeutic potential of L-asparaginase and allogeneic hematopoietic stem cell transplantation.

We conducted a retrospective Japan-Korea multicenter study to better elucidate the clinicopathologic features and therapeutic modalities for aggressive natural killer cell leukemia (ANKL). A total of 34 patients were analyzed. The median age of the patients was 40 years. Among the patients in the study, four had a history of Epstein-Barr virus-related disorders. Three types of ANKL cells were categorized according to their morphological features. Leukemic cells were below 20% in both peripheral blood and bone marrow of 11 patients. The clinical characteristics and prognoses of these 11 patients did not differ significantly from those of the others. As an initial therapy, l-asparaginase chemotherapy resulted in a better response. A total of six patients received allogeneic hematopoietic stem cell transplantation (HSCT) and two received autologous HSCT, with all in non-complete remission (CR). After HSCT, four with allogeneic and one with autologous HSCT reached CR. Median survival of all patients was 51 days. Median survival for the patients with and without HSCT were 266 and 36 days, respectively. A total of two patients with allogeneic HSCT were alive and in CR. All patients without HSCT died of ANKL. The use of L-asparaginase was indicated as a factor for longer survival (HR 0.33, 95% confidence interval; 0.13-0.83, P = 0.02). Early diagnosis of ANKL, l-asparaginase-based chemotherapy and allogeneic HSCT might lead to improved patient outcomes.

Lymphomatoid gastropathy: a distinct clinicopathologic entity of self-limited pseudomalignant NK-cell proliferation.

Diagnostic errors in distinguishing between malignant and reactive processes can cause serious clinical consequences. We report 10 cases of unrecognized self-limited natural killer-cell proliferation in the stomach, designated as lymphomatoid gastropathy (LyGa). This study included 5 men and 5 women (age, 46-75 years) without any gastric symptoms. Gastroscopy showed elevated lesion(s) (diameter, ∼ 1 cm). Histologically, medium-sized to large atypical cells diffusely infiltrated the lamina propria and, occasionally, the glandular epithelium. The cells were CD2(+/-), sCD3(-), cCD3(+), CD4(-), CD5(-), CD7(+), CD8(-), CD16(-), CD20(-), CD45(+), CD56(+), CD117(-), CD158a(-), CD161(-), T cell-restricted intracellular antigen-1(+), granzyme B(+), perforin(+), Epstein-Barr early RNA(-), T-cell receptor αß(-), and T-cell receptor γδ(-). Analysis of the 16 specimens biopsied from 10 patients led to a diagnosis of lymphoma or suspected lymphoma in 11 specimens, gastritis for 1 specimen, adenocarcinoma for 1 specimen, and LyGa or suspected LyGa for 3 specimens. Most lesions underwent self-regression. Three cases relapsed, but none of the patients died. According to conventional histopathologic criteria, LyGa is probably diagnosed as lymphoma, especially as extranodal natural killer/T-cell lymphoma, nasal type. However, LyGa is recognized as a pseudomalignant process because of its clinical characteristics. The concept of LyGa should be well recognized.

Identification of Bcl-2/IgH fusion sequences using real-time PCR and chip-based microcapillary electrophoresis.

BACKGROUND: The determination of polymerase chain reaction (PCR) amplification product sizes of the Bcl-2/IgH fusion gene from follicular lymphoma (FL) provides evidence of clonal identity. METHODS: The present study describes detection of Bcl-2/IgH fusion gene clonality utilizing a small, simple microcapillary electrophoretic chip combined with a real-time PCR method. RESULTS: The microcapillary electrophoretic chip system effectively detects size differences among the Bcl-2/IgH fusion gene amplification products of FL from patient samples; something that is not possible using traditional gel electrophoresis. We also describe the potential of this system to utilize formalin-fixed, paraffin-embedded tissue samples sectioned on charged slides. CONCLUSIONS: The simple detection of Bcl-2/IgH fusion gene clonality using a microcapillary electrophoretic chip provides reliable information for monitoring minimal residual disease of FL, and can be an effective tool for use in clinical laboratories.

Activity and safety of combination chemotherapy with methotrexate, ifosfamide, l-asparaginase and dexamethasone (MILD) for refractory lymphoid malignancies: a pilot study.

Optimal salvage chemotherapy has not been established for lymphoid malignancy, which is refractory to the conventional cyclophosphamide, doxorubicin, vincristine, and prednisone regimen. To explore an effective regimen, we conducted a phase I pilot study of combination chemotherapy with methotrexate, ifosfamide, l-asparaginase and dexamethasone (MILD), which are unaffected by MDR1-encoded P-glycoprotein. A total of 18 patients with lethal lymphoid malignancy were enrolled over a 2-yr period. The median age was 63 yr. Eleven patients had T/NK-cell malignancies, six had B-cell malignancies, and one was diagnosed with a blastic plasmacytoid dendritic cell neoplasm. Patients aged >/=60 and <60 yr were planned to receive a set of starting doses of methotrexate and ifosfamide, which should induce myelosuppression. Eleven patients completed two courses of MILD therapy. Treatment-related death because of systemic mucormycosis was observed in one patient. Major treatment-related adverse events were grade 3 or more hematologic toxicities, which included lymphopenia corresponding to dose-limiting toxicity. The most common grade 3 non-hematologic toxicity was febrile neutropenia. Of the 14 evaluated patients, three achieved a complete response, and four showed a partial response. The overall response rate was 57%. It was very interesting that all of seven responders had T/NK-cell malignancies. MILD therapy was feasible and presented acceptable toxicity in patients with refractory or lethal lymphoid malignancies. The efficacy for T/NK-cell malignancies should be further evaluated.

Light-chain amyloid myopathy isolated to skeletal muscles: A case report.

Isolated amyloidosis, especially of amyloid light-chain type, is an infrequent disease. Systemic chemotherapy for light-chain amyloidosis isolated to skeletal muscles plays a key role to reduce clonal plasma cells producing aberrant immunoglobulin.

Expression levels of apoptosis-related proteins and Ki-67 in nasal NK / T-cell lymphoma.

OBJECTIVES: Nasal natural killer (NK)/T-cell lymphoma is characterized by chemo-resistance, angiodestruction, and aggressive tumor progression. Few studies exist on molecular characteristics of this disease entity. METHODS: Expression levels of major apoptosis-related proteins Bcl-2, Bcl-x, Mcl-1, Bax, and a proliferative marker Ki-67 were analyzed in 11 nasal NK/T-cell lymphoma cases by immunohistochemical methods. Nine cases were of NK-cell lineage and two cases were of T-cell lineage. For comparison, 12 follicular lymphoma (FL) cases and 16 diffuse large B-cell lymphoma (DLBCL) cases were also studied. RESULTS AND CONCLUSIONS: Bax expression was low in all nasal NK-cell lymphoma cases, which constitute the major population of nasal NK/T-cell lymphoma. Bax expression in nasal NK-cell lymphoma was similar to FL and significantly lower compared with DLBCL. Bcl-2 expression was significantly lower in nasal NK/T-cell lymphoma compared with that of FL and DLBCL. Bcl-x expression was high in all three lymphomas. Two distinct Mcl-1 expression groups existed for nasal NK/T-cell lymphoma (6.2 +/- 5.2% and 59.1 +/- 12.3%, 95% CI). Ki-67 expression was high in nasal NK/T-cell lymphoma, and worse prognostic groups tended to express higher levels of Ki-67. The results suggest a combination of impaired apoptosis and aggressive proliferation in nasal NK/T-cell lymphoma, and may provide explanations for its poor prognosis.

Clinical analysis of 52 patients with granular lymphocyte proliferative disorder (GLPD) showed frequent anemia in indolent T-cell GLPD in Japan.

We present here clinical and hematological findings of 52 cases of granular lymphocyte-proliferative disorder (GLPD), which contained 35 indolent T-cell lineage granular lymphocyte-proliferative disorder (T-GLPD), two atypical T-GLPD, 12 chronic NK-cell lymphocytosis (CNKL), and three aggressive NK-cell leukemia (ANKL). The median period of follow up was 24 months. Hemoglobin level <8.0 g/dL was recognized in 21 cases of indolent T-GLPD (60%), among which 15 patients met the criteria of pure red cell aplasia. Neutrophil counts <500/microL occurred only in two cases of T-GLPD (6%). Although the median age and male-to-female distribution were similar, very frequent anemia and rare neutrocytopenia in indolent T-GLPD in the present study keenly contrasted with previous reports. CD56 was positive in three of 29 indolent T-GLPD cases with CD4-CD8+ phenotype, in three of four CD4+CD8-, and in none of two CD4-CD8- cases. Therefore, although two atypical T-GLPD cases were CD56-positive, CD56 should not be a specific marker for aggressive T-GLPD. All CNKL patients had a chronic course with a stable granular lymphocyte count. All three ANKL patients presented high fever and hepatosplenomegaly, barely responded to chemotherapies and died within 6 months. The present analysis of 52 cases of GLPD in Japan showed that Japanese and Western cases of indolent T-GLPD clearly differ in their hematological complications.

Ancient ubiquitous protein 1 and Syk link cytoplasmic tails of the integrin alpha(IIb)beta(3).

It is currently accepted that activity of the integrin alpha(IIb)beta(3) is modulated by direct interaction between its cytoplasmic tails (CTs) and association of cytoplasmic proteins with them, and disruption of the close linkage between CTs leads to activation of alpha(IIb)beta(3) (inside-out signaling). We previously reported that ancient ubiquitous protein (Aup1) binds to the membrane-proximal sequence of integrin alphaCTs that plays a pivotal role in the inside-out signaling. To explore biological function of Aup1, we examined in this study interaction of Aup1 with Src and Syk that are quickly activated in platelets before fibrinogen binding following thrombin stimulation. By immunoprecipitation assay with resting platelets, we first found that alpha(IIb)beta(3), Src, Syk, and Aup1 are constitutively complexed. In vitro binding study with recombinant Syk and glutathione (GSH) S-transferase (GST) - Src, -Aup1, and -alpha(IIb) and - beta(3) CTs that are immobilized to GSH- beads revealed direct binding of Syk to Aup1 as well as the beta(3) CT. Dot blot analysis with synthetic peptides for alpha(IIb) and beta(3) CTs, and GST-Aup1 and -Src immobilized to PVDF membrane exhibited concordant result with the GST pull-down assay. Immunoprecipitation of platelet lysates 10 seconds after thrombin stimulation, when activity and tyrosine phosphorylation of Syk are maimum, exhibited that active Syk does not coprecipitate with Aup1. In vitro kinase assay with GST-Syk and -Aup1 proteins at the presence or absence of active Src, a potent activator of Syk, revealed that Aup1 does not directly influence activation of Syk by autophosphorylation or tyrosine phosphorylation by Src. These results indicate that Aup1 is an adaptor recruiting Syk to the alpha(IIb) CT, and suggest that the alpha(IIb) -Aup1- Syk- beta(3) complex formation links alpha(IIb) and beta(3) CTs to sustain alpha(IIb)beta(3) in an inactive state and Syk dissociates from Aup1 after activation.

Phase I study of dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy for advanced-stage, relapsed or refractory extranodal natural killer (NK)/T-cell lymphoma and leukemia.

Extranodal natural killer (NK)/T-cell lymphoma, nasal type, and aggressive NK-cell leukemia are rare, and their standard therapy has not been established. They are Epstein-Barr virus-associated lymphoid malignancies, and tumor cells express P-glycoprotein leading to multidrug resistance of the disease. Patients with stage IV, relapsed or refractory diseases have a dismal prognosis, with survival measured in months only. To develop an efficacious chemotherapeutic regimen, we conducted a dose-escalation feasibility study of a new chemotherapeutic regimen, SMILE, comprising the steroid dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide. The components of SMILE are multidrug resistance-unrelated agents and etoposide. Etoposide shows both in vitro and in vivo efficacy for Epstein-Barr virus-associated lymphoproliferative disorders. Eligible patients had newly diagnosed stage IV, relapsed or refractory diseases after first-line chemotherapy, were 15-69 years of age, and had satisfactory performance scores (0-2). Four dose levels of methotrexate and etoposide were originally planned to be evaluated. At level 1, six patients with extranodal NK/T-cell lymphoma, nasal type, were enrolled. Their disease status was newly diagnosed stage IV (n = 3), first relapse (n = 2), and primary refractory (n = 1). All of the first three patients developed dose-limiting toxicities, and one of them died of sepsis with grade 4 neutropenia. A protocol revision stipulating early granulocyte colony-stimulating factor administration was made. Two out of three additional patients developed dose-limiting toxicities that were all manageable and transient. For the six enrolled patients, the overall response rate was 67% and the complete response rate was 50%. Although its safety and efficacy require further evaluation, we recommend a SMILE chemotherapy dose level of 1 for further clinical studies.

Autologous hematopoietic stem cell transplantation in extranodal natural killer/T cell lymphoma: a multinational, multicenter, matched controlled study.

Extranodal natural killer (NK)/T cell lymphoma, nasal type, is a recently recognized distinct entity and the most common type of non-B cell extranodal lymphoma in Asia. This retrospective analysis studied the potential survival benefits of hematopoeitic stem cell transplantation (HSCT) compared with a historical control group. A total of 47 patients from 3 previously published series of HSCT were matched according to NK/T cell lymphoma International Prognostic Index (NKIPI) risk groups and disease status at transplantation with 107 patients from a historical control group for analysis. After a median follow-up of 116.5 months, the median survival time was not determined for the HSCT group, but it was 43.5 months for the control group (95% confidence interval [CI] = 6.7 to 80.3 months; P = .127, log-rank test). In patients who were in complete remission (CR) at the time of HSCT or at surveillance after remission, disease-specific survival rates were significantly higher in the HSCT group compared with the control group (disease-specific 5-year survival rate, 87.3% for HSCT vs 67.8% for non-HSCT; P = .027). In contrast, in subgroup analysis on non-CR patients at the time of HSCT or non-HSCT treatment, disease-specific survival rates were not significantly prolonged in the HSCT group compared with the control group (1-year survival rate, 66.7% for HSCT vs 28.6% for non-HSCT; P = .141). The impact of HSCT on the survival of all patients was significantly retained at the multivariate level with a 2.1-fold (95% CI =1.2- to 3.7-fold) reduced risk of death (P = .006). HSCT seems to confer a survival benefit in patients who attained CR on postremission consolidation therapy. These findings suggest that, in particular, patients in CR with high NKIPI risk scores at diagnosis should receive full consideration for HSCT.

Changes in cell morphology and cytoskeletal organization are induced by human mitotic checkpoint gene, Bub1.

The mitotic spindle checkpoint prevents the onset of anaphase and subsequent cell division until chromosomes are properly aligned on a bipolar spindle. Thus, it regulates the cell division cycle by keeping cells with defective spindles from leaving mitosis. The budding uninhibited by benzimidazole (Bub1) is a key component of mitotic checkpoint. Bub1 encodes a serine/threonine kinase required for mitotic spindle checkpoint function. The regulation of cell morphology in eukaryotic cells is a complex process involving major components of the cytoskeleton including actin microfilaments, microtubules, and intermediate filaments (IFs). Here we show that Bub1 directly affects the structural integrity of IFs. Constitutive expression of Bub1 caused disappearance of filamentous vimentin, a type III IF, and consequently changed cell morphology. Expression of kinase domain-deleted Bub1 induced neither morphological change nor disappearance of vimentin. These observations suggest that Bub1 not only regulates the cell cycle, but also may be involved in the cytoskeletal control in interphase cells.

Long-term responses and outcomes following immunosuppressive therapy in large granular lymphocyte leukemia-associated pure red cell aplasia: a Nationwide Cohort Study in Japan for the PRCA Collaborative Study Group.

Large granular lymphocyte leukemia-associated pure red cell aplasia accounts for a significant portion of secondary pure red cell aplasia cases. However, because of its rarity, long-term responses and relapse rates after immunosuppressive therapy are largely unknown. We conducted a nationwide survey in Japan and collected 185 evaluable patients. Fourteen patients with large granular lymphocyte leukemia-associated pure red cell aplasia were evaluated. Cyclophosphamide, cyclosporine A and prednisolone produced remissions in 6/8, 1/4 and 0/2 patients respectively. Seven and 5 patients were maintained on cyclophosphamide or cyclosporine A respectively. Two patients relapsed after stopping cyclophosphamide, and 2 patients relapsed during maintenance therapy with cyclosporine A. The median relapse-free survival in the cyclophosphamide - and the cyclosporine A groups was 53 and 123 months respectively. Large granular lymphocyte leukemia-associated pure red cell aplasia showed a good response to either cyclophosphamide or cyclosporine A. Most patients continued to receive maintenance therapy and it remains uncertain whether cyclophosphamide or cyclosporine A can induce a maintenance-free hematologic response in large granular lymphocyte leukemia-associated pure red cell aplasia.