Kazutaka Ouchi

A novel XIAP mutation in a Japanese boy with recurrent pancytopenia and splenomegaly

X-linked lymphoproliferative syndrome (XLP) is a rare inherited primary immunodeficiency. It is clinically characterized by hemophagocytic lymphohistiocytosis (HLH), which usually develops in response to an Epstein-Barr virus (EBV) infection, dysgammaglobulinemia and malignant lymphoma. Most cases

Successful treatment of idiopathic colitis related to XIAP deficiency with allo-HSCT using reduced-intensity conditioning

Recently, it has been reported that Crohns‐like intractable colitis occurred in approximately 20% of the patients with XIAP deficiency, also known as X‐linked lymphoproliferative disease type 2. Because treatment used for Crohns disease is not always effective for Crohns‐like colitis related to XIAP deficiency, more effective treatment should be established. Although several studies reported allo‐HSCT might be promising even for Crohns‐like colitis related to XIAP deficiency, the outcome of allo‐HSCT using MAC for XIAP deficiency is extremely poor due to frequent TRM. In addition, there is little information about the outcome of allo‐HSCT for intractable colitis related to XIAP deficiency. Herein, we describe a patient with intractable colitis related to XIAP deficiency who was successfully treated with allo‐HSCT using a reduced‐intensity conditioning regimen. Although allo‐HSCT using the RIC regimen might be a curative therapeutic option for intractable colitis with XIAP deficiency, the prognostic factors that will determine the success of allo‐HSCT require further clinical information of more patients.

FN1: a novel fusion partner of ALK in an inflammatory myofibroblastic tumor.

Inflammatory myofibroblastic tumors (IMTs) are rare tumors characterized as low‐to‐intermediate grade sarcomas. Rearrangements of the anaplastic lymphoma kinase (ALK) gene have been reported in IMT. Here, we describe a novel fusion gene in an IMT tumor specimen. A 12‐year‐old male was admitted to our hospital with a bladder tumor. We identified the fibronectin 1 gene (FN1) as a fusion partner of ALK using 5′RACE. This novel fusion, FN1–ALK, resulted in ALK overexpression in the IMT. This finding should clarify the causes of IMT and facilitate development of novel therapeutics. Pediatr Blood Cancer 2015;62:909–911.

PAX3-NCOA2 fusion gene has a dual role in promoting the proliferation and inhibiting the myogenic differentiation of rhabdomyosarcoma cells

We analyzed a complex chromosomal translocation in a case of embryonal rhabdomyosarcoma (RMS) and showed that it generates the fusion gene PAX3 (paired box 3)-NCOA2 (nuclear receptor coactivator 2). To understand the role of this translocation in RMS tumorigenesis, we established two types of stable mouse myoblast C2C12 cell lines expressing PAX3-NCOA2 and PAX3-FOXO1A (forkhead box O1A), respectively. Compared with control cells, PAX3-NCOA2 cells grew faster, were more motile, were less anchorage dependent, progressed more quickly through the G1/S phase of cell cycle and showed greater transcriptional activation of the PAX3 consensus-binding site. However, PAX3-NCOA2 cells proliferated more slowly and differentiated more weakly than did PAX3-FOXO1A cells. Both PAX3-NCOA2 cells and PAX3-FOXO1A cells formed tumors in nude mice, although the PAX3-NCOA2-induced tumors grew more slowly. Our results may explain why NCOA2 rearrangement is mainly found in embryonal rhabdomyosarcoma, which has a better prognosis than alveolar rhabdomyosarcoma, which expresses the PAX3-FOXO1A fusion gene. These results indicate that the PAX3-NCOA2 fusion gene has a dual role in the tumorigenesis of RMS: promotion of the proliferation and inhibition of the myogenic differentiation of RMS cells.

A NOXA/MCL‐1 Imbalance Underlies Chemoresistance of Malignant Rhabdoid Tumor Cells

Malignant rhabdoid tumor (MRT) is a rare aggressive pediatric cancer characterized by inactivation of SNF5, a core subunit of SWI/SNF complexes. Previously, we showed that SNF5 contributes to transcriptional activation of NOXA, a pro‐apoptotic protein that binds and inhibits the anti‐apoptotic protein MCL‐1. In this study, we found that NOXA expression was downregulated in MRT cell lines as well as in clinical MRT samples and that ectopically expressed NOXA bound MCL‐1 and increased the sensitivity of MRT cell lines to doxorubicin (DOX) by promoting apoptosis. Consistent with this finding, knockdown of MCL‐1 in MRT cell lines induced apoptosis and increased DOX sensitivity in MRT cells, and the MCL‐1 inhibitor TW‐37 synergized with DOX to induce MRT cell death. Our results suggest that modulation of the NOXA/MCL‐1 pathway may be a potential strategy for the treatment of patients with MRT. J. Cell. Physiol. 231: 1932–1940, 2016.

Secondary neuroendocrine tumor after allogeneic bone marrow transplantation.

Here we report a case of aggressive neuroendocrine tumor (NET), which is an extremely rare secondary solid tumor that occurs after allogeneic hematopoietic cell transplantation (allo‐HSCT). A patient with chronic active Epstein–Barr virus infection received allo‐HSCT from an HLA‐DR two allele‐mismatched unrelated donor. Four years later, he developed NET with multiple metastases. He received thoraco‐abdominal irradiation as a conditioning regimen, and developed repeated episodes of intestinal graft‐versus‐host disease, for which he received long‐term immunosuppressive therapy. Although these factors may be potential contributing factors to the development of secondary NET, the exact pathogenesis remains unclear.

Neoadjuvant Treatment With Cyclooxygenase-2 Inhibitor and Prednisolone Allows Conservative Surgery for Inflammatory Myofibroblastic Tumor of the Bladder.

Inflammatory myofibroblastic tumor (IMT), which expresses cyclooxygenase-2 (COX-2), can be effectively treated with COX-2 inhibitor. Here, we report a case of urinary bladder IMT in a 13-year-old boy. Although total cystectomy was initially planned for complete resection of the tumor, neoadjuvant treatment with COX-2 inhibitor and prednisolone reduced the size of the tumor and enabled complete resection of the tumor by partial cystectomy. Neoadjuvant treatment with COX-2 inhibitor and prednisolone for IMT of the bladder allowed a more conservative surgical procedure that preserved bladder function.