Abnormalities of chromosome 7q are common in myeloid malignancies, but no specific target genes have yet been identified. Here, we describe the finding of homozygous EZH2 mutations in 9 of 12 individuals with 7q acquired uniparental disomy. Screening of a total of 614 individuals with myeloid disorders revealed 49 monoallelic or biallelic EZH2 mutations in 42 individuals; the mutations were found most commonly in those with myelodysplastic/myeloproliferative neoplasms (27 out of 219 individuals, or 12%) and in those with myelofibrosis (4 out of 30 individuals, or 13%). EZH2 encodes the catalytic subunit of the polycomb repressive complex 2 (PRC2), a highly conserved histone H3 lysine 27 (H3K27) methyltransferase that influences stem cell renewal by epigenetic repression of genes involved in cell fate decisions. EZH2 has oncogenic activity, and its overexpression has previously been causally linked to differentiation blocks in epithelial tumors. Notably, the mutations we identified resulted in premature chain termination or direct abrogation of histone methyltransferase activity, suggesting that EZH2 acts as a tumor suppressor for myeloid malignancies.

Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders

Prognostic Significance of T-Cell Phenotype in Aggressive Non-Hodgkin's Lymphomas

Cyclosporin is a lipophilic cyclic polypeptide which produces calcium-dependent, specific, reversible inhibition of transcription of interleukin-2 and several other cytokines, most notably in T helper lymphocytes. This reduces the production of a range of cytokines, inhibiting the activation and/or maturation of various cell types, including those involved in cell-mediated immunity. Thus, cyclosporin has immunosuppressive properties, and has a proven place as first line therapy in the prophylaxis and treatment of transplant rejection. Cyclosporin has also been evaluated in a large range of disorders where immunoregulatory dysfunction is a suspected or proven aetiological factor, and this is the focus of the present review. In patients with severe disease refractory to standard treatment, oral cyclosporin is an effective therapy in acute ocular Behcet's syndrome, endogenous uveitis, psoriasis, atopic dermatitis, rheumatoid arthritis, active Crohn's disease and nephrotic syndrome. Concomitant low dose corticosteroid therapy may improve response rates in some disorders. The drug can be considered as a first line therapy in patients with moderate or severe aplastic anaemia who are ineligible for bone marrow transplantation, with the additional benefit of reducing platelet alloantibody titres. It may also be of considerable therapeutic benefit in patients with primary biliary cirrhosis, particularly those with less advanced disease. Limited evidence suggests cyclosporin is effective in patients with intractable pyoderma gangrenosum, polymyositis/dermatomyositis or severe, corticosteroid-dependent asthma. Indeed, the steroid-sparing effect of cyclosporin is a significant advantage in a number of indications. Furthermore, the drug has shown some efficacy in a wide range of other, generally uncommon disorders in which controlled clinical trials are lacking and/or are unlikely to be performed. Cyclosporin does not appear to be effective in patients with allergic contact dermatitis, multiple sclerosis or amyotrophic lateral sclerosis. It is only temporarily effective in patients with type I (insulin-dependent) diabetes mellitus and should not be used in this indication. To avoid relapse after control of active disease, patients should receive cyclosporin maintenance therapy at the lowest effective dosage. However, maintenance therapy appears to be of no benefit in patients with Crohn's disease and cyclosporin should be discontinued in these patients once active disease is controlled. Hypertrichosis, gingival hyperplasia, and neurological and gastrointestinal effects are the most common adverse events in cyclosporin recipients, but are usually mild to moderate and resolve on dosage reduction. Changes in laboratory variables indicating renal dysfunction are relatively common, although serious irreversible damage is rare.(ABSTRACT TRUNCATED AT 400 WORDS)

/pdf/cyclosporin-a-review-of-its-pharmacodynamic-and-2wjzyh5l5a.pdf

Cyclosporin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in immunoregulatory disorders.

Neoplastic T cells in angioimmunoblastic T-cell lymphoma express CD10

Angioimmunoblastic T-cell lymphoma (AITL) is one of the most common types of T-cell lymphoma, representing about 15–20% of cases of peripheral T-cell lymphoma (PTCL). It is characterized by a unique clinical presentation and distinct pathologic and molecular features. Classes of drugs particularly active in AITL are emerging; however, treatment of relapsed and refractory disease remains a challenge. This chapter reviews the epidemiology, clinical presentation, pathogenesis, diagnosis, and treatment of AITL.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1365-2141.2003.04335.x

Angioimmunoblastic T‐cell lymphoma

A novel cell line SKNO-1 was established from the bone marrow cells of a 22-year-old male suffering from acute myeloblastic leukaemia (AML) M2 with t(8;21) whose disease became resistant to chemotherapy after acquisition of 17 monosomy. SKNO-1 has been maintained for more than 36 months as a granulocyte-macrophage colony-stimulating factor (GM-CSF) dependent line.

Morphologically, SKNO-1 cells were myeloblasts somewhat maturated. The cells grow in suspension with a doubling time of 48-72 h. The survival and growth of SKNO-1 cells was absolutely dependent on granulocyte-macrophage colony stimulating factor (GM-CSF). SKNO-1 cells possessed t(8;21) and monosomy 17 which were observed in original leukaemic cells. We confirmed that the AML1 gene, located on chromosome 21, was rearranged and the AML1-MTG8 fusion transcript was expressed in SKNO-1 cells. Over-expression and mutation of the p53 gene were also detected in SKNO-1. It is likely that alterations of AML1 or MTG8 gene and p53 gene contribute to a disease progression in this case.

Since t(8;21) translocation is a common chromosome abnormality in AML, and inactivation of the p53 gene may play a crucial role in disease progression in AML, SKNO-1 would be a useful tool for analysing the molecular mechanisms in myeloid leukaemogenesis.

Establishment of a myeloid leukaemic cell line (SKNO‐1) from a patient with t(8;21) who acquired monosomy 17 during disease progression

Angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) is a lymphoma-like disease. Although the histologic appearance of this disease is benign, it is clinically malignant, with chemotherapy being ineffective and the prognosis being poor. In this article, the authors report the results of treating two patients with AILD with cyclosporin A. One patient had cervical lymphadenopathy and fever, and AILD was refractory to both chemotherapy and alpha-interferon. However, treatment with cyclosporin A achieved complete remission. The other patient had generalized lymphadenopathy, and cyclosporin A was used as the treatment of first choice. Complete remission also was achieved in this patient, who still is in remission. These two cases demonstrate that cyclosporin A can be effective for treating AILD.

Successful treatment of angioimmunoblastic lymphadenopathy with dysproteinemia with cyclosporin A

Summary. A cell line designated SKM-1 was newly established from leukaemic cells of a 76-year-old Japanese male patient with monoblastic leukaemia following myelodysplastic syndrome (MDS). The cells were obtained from peripheral blood of the patient when he lost multiple point mutations of ras genes with acquisition of chromosomal abnormalities during disease progression in MDS. The cells grew as a single floating cell, and have been continuously growing with the morphological characteristics of immature monoblasts by serial passages during the past 42 months with a doubling time of about 48 h. By cytochemical analysis. the cloned cells were positive for butyrate esterase, but negative for the Epstein-Barr virus associated nuclear antigen. Phenotypic analysis revealed the expression of myelomonocyte specific antigens such as CD4, CD13, CD33 and HLA-DR. Cells from the primary peripheral blood and those from SO passages of the SKM-1 cell line both possessed no activated ras genes but showed karyotype abnormalities with 46.XY, del(9)(q13;q22), der(17) t(17:?)(p13:?). The SKM-1 cells have two mutations in p53 gene and overexpress the pS3 products. This cell line may contribute to a better understanding of molecular mechanisms in the progression from MDS to myelogenous leukaemia.

Establishment of a leukaemic cell line from a patient with acquisition of chromosomal abnormalities during disease progression in myelodysplastic syndrome

Although molecular and cytogenetic studies strongly point to the role of oncogenes, the mechanisms underlying the development of MDS and their progressive evolution to AML are still largely unknown. It has been postulated that AML has a preleukemic stage and a multi step pathogenesis, with the preleukemic stem cell able to undergo clonal evolution, with the acquisition of karyotypic abnormalities, leading to the development of acute leukemic subclones. The activations of the ras oncogenes or inactivation of the p53 anti-oncogene by point mutations have been described recently in several cases of MDS as well as AML, suggesting a critical role for these alterations in the development of these myelogenous leukemias. We reported previously establishment of a leukemic cell line, SKM-1, from the patient who initially possessed multiple point mutations of ras genes but lost these mutations during disease progression to myelomonocytic leukemia with acquisition of chromosomal abnormalities involving the p53 anti-oncogene. This process is characterized by genetic instabilities probably due to the failure of their DNA repairment leading to abnormal control of cell proliferation and differentiation. Studying this cell line, SKM-1, is a promising approach to understand the mechanisms of the initiation, disease progression, alterations of DNA repairment, and genetic instability in MDS and myelogenous malignancies.

The SKM-1 leukemic cell line established from a patient with progression to myelomonocytic leukemia in myelodysplastic syndrome (MDS)-contribution to better understanding of MDS.

Sachiko Matozaki

Papers

Establishment of a myeloid leukaemic cell line (SKNO‐1) from a patient with t(8;21) who acquired monosomy 17 during disease progression

Successful treatment of angioimmunoblastic lymphadenopathy with dysproteinemia with cyclosporin A

Establishment of a leukaemic cell line from a patient with acquisition of chromosomal abnormalities during disease progression in myelodysplastic syndrome

The SKM-1 leukemic cell line established from a patient with progression to myelomonocytic leukemia in myelodysplastic syndrome (MDS)-contribution to better understanding of MDS.

Idiopathic thrombocytopenic purpura with X chromosome abnormality