Shio Sakai

Successful combination treatment with bevacizumab, thalidomide and autologous PBSC for severe POEMS syndrome

Successful combination treatment with bevacizumab, thalidomide and autologous PBSC for severe POEMS syndrome

Identification of a novel TEL–Lyn fusion gene in primary myelofibrosis

Myeloproliferative neoplasms (MPNs) are a heterogeneous group of diseases characterized by an excessive production of blood cells by hematopoietic precursors and are often accompanied by myelofibrosis. The V617F somatic mutation in the Janus kinase 2 gene (JAK2) has recently been found in the majority of patients with polycythemia vera, in 60–70% of patients with essential thrombocythemia and in approximately 50% of patients with primary myelofibrosis (PMF). The expression of JAK2 V617F causes a polycythemia vera-like disease with associated myelofibrosis in a murine bone marrow (BM) transplant model. In addition, a gain-of-function c-MPL W515 mutation was described in nearly 10% of patients with JAK2 V617F-negative PMF. However, the mechanism responsible for MPN and for the formation of myelofibrosis in patients without the JAK2 or c-MPL mutation is still unclear. The TEL gene is a member of the ets family transcription factor located on the 12p13 chromosome. It is well known that TEL forms fusion genes with more than 20 partner genes in hematological and even nonhematological malignancies. A major group of TEL fusion partners includes protein tyrosine kinases (PTK) and transcriptional factors such as RUNX1 (AML1) in childhood leukemia. The former group includes fusions of TEL to ABL, ARG, JAK2, NTRK3, FGFR3, PDGFR-a and Syk kinase, which have been found in MPN and other hematological malignancies. The most precisely defined mechanism of transformation by TEL–PTK fusion products is through a constitutive kinase activation by oligomerization of TEL–PTK mediated by the PNT domain of TEL in TEL–PTK chimeras. Lyn kinase is a specific member of the src family of kinases and is an important component in cytokine signal transduction in a variety of cells; it is also reported to have a key role in the growth and apoptotic regulation of hematopoietic cells. Donato et al. reported that Lyn kinase is highly expressed and activated in imatinib-resistant K562 cells and in samples from chronic myeloid leukemia patients who progressed to a blastic crisis or to an accelerated phase during imatinib treatment. In addition, Lyn is constitutively activated in acute myeloid leukemia and in BCR-ABL-positive acute lymphoblastic leukemia. However, there has been no report of the src family tyrosine kinase gene fusing to TEL and a possible association with MPN. In this study, we identified a novel TEL–Lyn fusion gene in PMF bearing the chromosomal abnormality ins (12;8)(p13;q11q21), and analyzed its mitogenic and clonogenic capacity. A 21-year-old man developed a huge abdominal mass, pain and high fever and was admitted to a hospital in November 2004. His physical examination revealed a huge splenomegaly reaching to his pelvic cavity. Laboratory findings disclosed

Successful treatment by azacitidine therapy of intestinal Behçet’s disease associated with myelodysplastic syndrome

Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic stem cell diseases. It has been reported that several autoimmune diseases are associated with MDS. Recently, the co-occurrence of MDS with trisomy 8 and rare disorders of the immune system, such as Behçet’s disease (BD), has been described. Prognosis in the older-onset group of MDS-associated BD is unfavorable. Here, we report a case of MDS-associated intestinal BD treated successfully by azacitidine therapy. A 59-year-old Japanese male suffering from recurrent high fever, melena, and oral and genital ulcerations was diagnosed with MDS with trisomy 8 and intestinal BD by endoscopic and bone marrow examinations. Immunosuppressive therapies, including infliximab, were ineffective. Due to his severe emphysema, the patient was considered ineligible for stem cell transplantation, and azacitidine therapy was initiated. With the exception of fever, the symptoms of intestinal BD improved, and severe malnutrition and anemia were ameliorated. Fluorescence in situ hybridization analyses of the bone marrow before the eighth cycle revealed that the trisomy 8 had not decreased. To our knowledge, this is the first report of azacitidine therapy for MDS-associated BD. We suggest that azacitidine may control intestinal BD by mechanisms other than those responsible for its effect in MDS.

Tetraspanin CD9 modulates ADAM17-mediated shedding of LR11 in leukocytes.

LR11, also known as SorLA or SORL1, is a type-I membrane protein from which a large extracellular part, soluble LR11 (sLR11), is released by proteolytic shedding on cleavage with a disintegrin and metalloproteinase 17 (ADAM17). A shedding mechanism is presumed to have a key role in the functions of LR11, but the evidence for this has not yet been demonstrated. Tetraspanin CD9 has been recently shown to regulate the ADAM17-mediated shedding of tumor necrosis factor-α and intercellular adhesion molecule-1 on the cell surface. Here, we investigated the role of CD9 on the shedding of LR11 in leukocytes. LR11 was not expressed in THP-1 monocytes, but it was expressed and released in phorbol 12-myristate 13-acetate (PMA)-induced THP-1 macrophages (PMA/THP-1). Confocal microscopy showed colocalization of LR11 and CD9 proteins on the cell surface of PMA/THP-1. Ectopic neo-expression of CD9 in CCRF-SB cells, which are LR11-positive and CD9-negative, reduced the amount of sLR11 released from the cells. In contrast, incubation of LR11-transfected THP-1 cells with neutralizing anti-CD9 monoclonal antibodies increased the amount of sLR11 released from the cells. Likewise, the PMA-stimulated release of sLR11 increased in THP-1 cells transfected with CD9-targeted shRNAs, which was negated by treatment with the metalloproteinase inhibitor GM6001. These results suggest that the tetraspanin CD9 modulates the ADAM17-mediated shedding of LR11 in various leukemia cell lines and that the association between LR11 and CD9 on the cell surface has an important role in the ADAM17-mediated shedding mechanism.

Severe hyponatremia caused by syndrome of inappropriate secretion of antidiuretic hormone developed as initial manifestation of human herpesvirus‐6–associated acute limbic encephalitis after unrelated bone marrow transplantation

Severe hyponatremia is a critical electrolyte abnormality in allogeneic stem cell transplantation (allo‐SCT) recipients and >50% of cases of severe hyponatremia are caused by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Here, we present a patient with rapidly progressive severe hyponatremia as an initial sign and symptom of human herpesvirus‐6–associated post‐transplantation acute limbic encephalitis (HHV‐6 PALE) after allo‐SCT. A 45‐year‐old woman with acute lymphoblastic leukemia received unrelated bone marrow transplantation from a one locus‐mismatched donor at the DR locus. On day 21, she developed a generalized seizure and loss of consciousness with severe hyponatremia, elevated serum antidiuretic hormone (ADH), and decreased serum osmolality. A high titer of HHV‐6 DNA was detected in cerebrospinal fluid. Treatment with foscarnet sodium and hypertonic saline was started with improvement of neurological condition within several days. Although an elevated serum ADH, low serum osmolality, and high urinary osmolality persisted for 2 months, she had no other recurrent symptoms of encephalitis. Our experience suggests that hyponatremia accompanied by SIADH should be recognized as a prodromal or concomitant manifestation of HHV‐6 PALE, and close monitoring of serum sodium levels in high‐risk patients for HHV‐6 PALE is necessary for immediate diagnosis and treatment initiation.

Posterior reversible encephalopathy syndrome in an adult patient with acute lymphoblastic leukemia after remission induction chemotherapy

Posterior reversible encephalopathy syndrome (PRES) has been reported in childhood leukemia patients increasingly frequently. However, the development of PRES in adult leukemia patients during chemotherapy is very rare. We present a case of PRES in an adult patient with acute lymphoblastic leukemia (ALL) after remission induction chemotherapy. A 28-year-old woman with ALL was administered remission induction chemotherapy consisting of cyclophosphamide, daunorubicin, vincristine, prednisone, and l-asparaginase. After initiation of chemotherapy, the patient developed paralytic ileus and hypertension, and on day 30, she suddenly developed generalized convulsions, loss of visual acuity, and muscle weakness in the legs. Magnetic resonance imaging findings and her signs and symptoms were typical of PRES. The symptoms gradually improved following treatment with an anticonvulsant and an antihypertensive agent, and the patient underwent allogeneic bone marrow transplantation. She has completely recovered from PRES and has been asymptomatic without leukemia relapse. During remission induction chemotherapy for ALL, PRES may be caused by multiple drugs, such as l-asparaginase, vincristine, and corticosteroids, with different mechanisms of action. PRES should be recognized as an important complication, which will occur more frequently with the increased intensity of chemotherapy for adult ALL patients.

LR11: a novel biomarker identified in follicular lymphoma

Follicular lymphoma (FL) is the second most frequent type of non-Hodgkin lymphoma and is incurable by combination chemotherapies (Salles & Ghesquieres, 2012). Although the Follicular Lymphoma International Prognostic Index-2 (FLIPI-2) is predictive for progression-free survival (PFS) (Federico et al, 2009), widely adapted biomarkers that are directly released from FL tumour cells have not been established to date. LR11 (also called SORL1 or SorLA) is a type I membrane protein that plays a key role in the migration of undifferentiated vascular smooth muscle cells (Jiang et al, 2008), and circulating soluble LR11 (sLR11) is a biomarker for coronary stenosis (Takahashi et al, 2010). The potent action of sLR11 is mediated by the urokinase-type plasminogen activator receptor (uPAR)/integrin-mediated activation of focal adhesion kinase (FAK)/ERK/Rac1 cascades (Ohwaki et al, 2007). LR11 is also expressed in human CD34CD38 immature haematopoietic precursors (Zhang et al, 2000), but little is known about its potential role in haematopoietic cells. We have recently found that LR11 is highly expressed in leukaemic cells and that serum sLR11 levels in acute leukaemia patients are significantly increased at diagnosis and normalize at remission (Sakai et al, 2012). Here we analysed the expression profile of LR11 in FL cells and evaluated the clinical importance of serum sLR11 levels in FL patients. Tumour specimens and serum samples were collected from 61 newly diagnosed, untreated FL patients attending Chiba University Hospital and affiliated hospitals between 2002 and 2012. Fifty-two patients (85.2%) were treated with the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) regimen, 3 (4.9%) with irradiation only, and 6 (9.8%) were observed without treatment (see Table SI for patients’ characteristics). Paired serum samples at diagnosis and remission were obtained in 20 patients. Normal controls were serum samples collected from 75 healthy adult volunteers who had given informed consent.

Factors associated with the efficiency of PBSC collection in POEMS syndrome patients undergoing autologous PBSC transplantation

Factors associated with the efficiency of PBSC collection in POEMS syndrome patients undergoing autologous PBSC transplantation

Mobilization of PBSCs in poor mobilizers with POEMS syndrome using G-CSF with plerixafor

Auto-SCT has been established as an effective treatment for patients with hematological malignancies such as lymphoma or myeloma. Unfortunately, some patients fail to mobilize a sufficient number of PBSCs for transplantation. Plerixafor is the first molecule to reversibly inhibit the binding of chemokine stromal cell-derived factor-1α (SDF-1α) to its cognate receptor, CXCR4.1 Many recent reports have shown that there is a potential clinical application for plerixafor in PBSC harvesting.2, 3, 4, 5, 6

Low-dose trimethoprim-sulfamethoxazole for Pneumocystis jiroveci pneumonia prophylaxis after allogeneic hematopoietic SCT.

Low-dose trimethoprim–sulfamethoxazole for Pneumocystis jiroveci pneumonia prophylaxis after allogeneic hematopoietic SCT