IntroductionInterferon ␣ (IFN-␣) is an important therapeutic cytokine that exerts antitumor activity in a variety of tumor cells. 1,2 Chronic myelogenous leukemia (CML) is one of the hematologic malignancies that responds well to IFN-␣ therapy. [3][4][5] However, the effect of the therapy is limited because of the development of resistance to IFN-␣, which has often been observed in patients with CML in the late chronic phase, accelerated phase, or blastic phase. 5 Although efforts to understand the molecular basis of the resistance to IFN-␣ have been made, the mechanism is still unknown.Interferon ␣ exerts its biologic actions by binding to the high-affinity cell surface receptor. Receptor-associated Janus family tyrosine kinases Tyk2 and Jak1 are activated on stimulation by IFN-␣, followed by tyrosine phosphorylation of critical tyrosine residues of the cytoplasmic domain of the receptors by Jaks. 6 This allows receptor recruitment and Jak-mediated tyrosine phosphorylation of signal transducer and activator of transcription (STAT) molecules. When STAT1 and STAT2 become tyrosine phosphorylated they bind to each other and, in combination with p48, form a complex called IFN-stimulated gene factor-3 (ISGF3). After translocation into the cell nucleus, this complex binds to the conserved IFN-stimulated responsive element (ISRE) sequence within the promoter of IFN-responsive genes and initiates transcription of these genes. 7 The suppressor of cytokine signaling (SOCS) proteins, 8 also known as STAT-induced STAT inhibitor (SSI) 9 or cytokineinducible src homology (SH)2 domain-containing protein (CIS), 10 are a family of negative regulators of cytokine signaling that are characterized by a central SH2 domain and a C-terminal SOCSbox. 11 Of the family members, SOCS1 and SOCS3 are the most potent inhibitors of cytokine-induced signals. Forced expression of SOCS1 or SOCS3 down-regulates a variety of cytokine signal pathways including Previously, we established a new human CML cell line, KT-1, from the peripheral blood of a patient with CML blast crisis. 13 Although most CML cell lines are resistant to IFN-␣, this cell line is sensitive to the antiproliferative and apoptosis-inducing effects of IFN-␣. Subsequently, we established several sublines of the KT-1 cell line. 14,15 These sublines exhibit significant variation in responsiveness to IFN-␣. One subline, KT-1/A3, is the most sensitive cell line against IFN-␣ treatment. One of the IFN-␣-resistant sublines, KT-1/B7, was isolated by subcloning of KT-1 cells without any selection by IFN-␣ treatment. 14 Another IFN-␣-resistant cell line, KT-1/A3R, was isolated by culturing KT-1/A3 cells with increasing concentrations of IFN-␣. 15 In both of these IFN-␣-resistant sublines, IFN-␣-induced activation of ISGF3 was reduced in comparison with KT-1/A3 cells. In the KT-1/B7 subline, the level of STAT2 protein (one of the ISGF3 components) was reduced and this reduction was responsible for the reduced ISGF3 activation by IFN-␣. In the KT-1/A3R subline, the ISGF3 components were unc...

The t(1;21)(p36;q22) is a recurrent chromosome abnormality associated with therapy-related acute myeloid leukemia (AML). Although involvement of RUNX1 has been detected by fluorescence in situ hybridization analysis, the partner gene has not been reported previously. We identified a novel RUNX1 partner gene, MDS1/EVI1-like-gene 1 (PRDM16), in an AML patient with t(1;21). Alternative splicing of the fusion gene generates five different fusion transcripts. In two of them, the PRDM16 reading frame is maintained in the fusion with RUNX1, suggesting that the RUNX1-PRDM16 gene fusion results in the production of a protein that is highly homologous to the RUNX1-MDS1/EVI1 chimeric protein. It is suggested that PRDM16 and MDS1/EVI1 share a common molecular mechanism for the leukemogenesis of RUNX1-associated leukemia. Characterization of the RUNX1-PRDM16 fusion protein and comparison with the RUNX1-MDS1/EVI1 protein will facilitate the understanding of the mechanisms underlying RUNX1-associated leukemia.

Summary:A 61-year-old man with angioimmunoblastic lymphoma in first complete remission underwent autologous peripheral blood stem cell transplantation. At 1 month post transplant, asymptomatic large granular lymphocytosis developed. The surface marker profile of the cells was CD3 þ CD8 þ CD56ÀCD57 þ . The disease course was chronic and indolent. The patient remains in complete remission from angioimmunoblastic lymphoma more than 6 months post transplant with persistent large granular lymphocytosis (lymphocyte count, 5-15 Â 10 9 /l). Although post transplantation T-cell lymphoproliferative disorders have mostly occurred in allogeneic transplantation recipients and presented as aggressive lymphomas/leukemias, we suggest that chronic indolent T-cell large granular lymphocytic leukemia can occur after autologous stem cell transplantation. Bone Marrow Transplantation (2004) 33, 99-101. doi:10.1038/sj.bmt.1704298 Keywords: T-cell large granular lymphocytic leukemia; post transplantation lymphoproliferative disorders; autologous peripheral blood stem cell transplantation T-cell large granular lymphocytic (T-LGL) leukemia is a lymphoproliferative disease derived from post-thymic immunocompetent T lymphocytes. 1 Large granular cell morphology, CD3 þ CD56ÀCD57 þ immunophenotype and the clonal rearrangement of T-cell receptor genes characterize T-LGL leukemia, which presents clinically with a chronic indolent disease course, complicated by frequent infections secondary to neutropenia.Post transplantation lymphoproliferative disorders (PTLD) are a well-recognized complication of solid organ and allogeneic bone marrow transplantation, and accumulating data have suggested that aggressive immunosuppression is closely associated with an increased risk of PTLD. 2,3 The majority of PTLD are of B-cell origin and are associated with active infection with Epstein-Barr virus (EBV). T-cell PTLD are much less common but, similar to B-cell PTLD, they mostly present as aggressive lymphomas following a rapidly fatal course. 4,5 EBV is infrequently involved in the pathogenesis. Autologous stem cell transplantation (ASCT) is another transplantation procedure. In spite of the profound myelosuppression associated with autografting, this procedure is inherently less immunosuppressive than allogeneic bone marrow transplantation and we were able to find less than 20 cases in the English literature describing PTLD following ASCT. 6-8 Here, we report the first case of chronic T-LGL leukemia following ASCT for angioimmunoblastic lymphoma. Case reportA 61-year-old man was admitted to our hospital in April 1997 because of fever, skin rash, edema, generalized lymphadenopathy and hemolysis. On physical examination, there was a maculo-papular rash on the trunk and extremities, and superficial lymphadenopathy was found in various regions including the neck, axilla and groin. A left pleural effusion and moderate splenomegaly (20 mm on the left midclavicular line) were also noted. The hemoglobin (Hb) was 8.1 g/dl, white blood cell count (WBC) 9.1 Â 10 9 /l...

A 29-year-old man developed diffuse large B-cell lymphoma in a subpectoral pacemaker pocket that 6 years previously had been created in the chest for a titanium-covered pulse generator. The patient had an 8-cm-diameter dark red tumor with necrotic tissue on a keloidal surgical scar in the left side of the chest. Left axillary lymphadenopathy also was present. Laboratory studies showed an increased level of soluble interleukin 2 receptor and a normal level of lactose dehydrogenase. A biopsy specimen showed a diffuse large B-cell phenotype and monoclonal immunoglobulin H gene rearrangement. A gallium scintigraphy study showed abnormal accumulation in the left chest and left axilla. On the basis of these findings, we diagnosed diffuse large B-cell lymphoma, stage II. The patient received THP-COP chemotherapy (pirarubicin, cyclophosphamide, vincristine, and prednisolone) and radiotherapy, achieved complete remission, and was free of disease for 16 months after treatment. This case suggests that there was a relationship between the development of non-Hodgkin's lymphoma and the presence of chronic inflammation in the pulse generator pocket.

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