CBL, CBLB, TET2, ASXL1, and IDH1/2 mutations and additional chromosomal aberrations constitute molecular events in chronic myelogenous leukemia

Progression of chronic myelogenous leukemia (CML) to accelerated (AP) and blast phase (BP) is because of secondary molecular events, as well as additional cytogenetic abnormalities. On the basis of the detection of JAK2, CBL, CBLB, TET2, ASXL1, and IDH1/2 mutations in myelodysplastic/myeloproliferative neoplasms, we hypothesized that they may also contribute to progression in CML. We screened these genes for mutations in 54 cases with CML (14 with chronic phase, 14 with AP, 20 with myeloid, and 6 with nonmyeloid BP). We identified 1 CBLB and 2 TET2 mutations in AP, and 1 CBL, 1 CBLB, 4 TET2, 2 ASXL1, and 2 IDH family mutations in myeloid BP. However, none of these mutations were found in chronic phase. No cases with JAK2V617F mutations were found. In 2 cases, TET2 mutations were found concomitant with CBLB mutations. By single nucleotide polymorphism arrays, uniparental disomy on chromosome 5q, 8q, 11p, and 17p was found in AP and BP but not involving 4q24 (TET2) or 11q23 (CBL). Microdeletions on chromosomes 17q11.2 and 21q22.12 involved tumor associated genes NF1 and RUNX1, respectively. Our results indicate that CBL family, TET2, ASXL1, and IDH family mutations and additional cryptic karyotypic abnormalities can occur in advanced phase CML.     

Thermodynamic Investigation of Inhibitor Binding to 1-Deoxy-d-Xylulose-5-Phosphate Reductoisomerase

d-xylulose-5-phosphate reductoisomerase (DXR), a target for developing novel anti-infectives. The binding of hydroxamate inhibitors to Escherichia coli DXR is Mg²⁺-dependent, highly endothermic (ΔH, 22.7–24.3 kJ/mol), and entropy-driven, while that of nonhydroxamate compounds is metal ion-independent and exothermic (ΔH, −19.4 to −13.8 kJ/mol), showing that hydration/dehydration of the enzyme metal ion binding pocket account for the drastic ΔH change. However, for DXRs from Plasmodium falciparum and Mycobacterium tuberculosis, the binding of all inhibitors is exothermic (ΔH, −24.9 to −9.2 kJ/mol), suggesting that the metal ion binding sites of these two enzymes are considerably less hydrated. The dissociation constants measured by ITC are well correlated with those obtained by enzyme inhibition assays (R² = 0.75). Given the rapid rise of antibiotic resistance, this work is of interest since it provides novel structural implications for rational development of potent DXR inhibitors.     

Mycophenolate mofetil (MMF) treatment efficacy in children with primary and secondary glomerulonephritis

Introduction

The aim of our study was to analyse the efficacy and safety of mycophenolate mofetil (MMF) as part of the complex immunosuppressive therapy in children with different types of primary and secondary glomerulonephritis, who were not eligible for the standard treatment routine suggested by evidence-based guidelines.

Material and methods

The study group comprised 85 children with proteinuric glomerulopathies hospitalized between 2007 and 2010, who were non-responders to immunosuppressive therapy. The dose of MMF was established as 1 g/m²/24 h. Remission was defined as negative proteinuria in three consecutive urinalyses.

Results

The patients were divided into 4 groups: idiopathic nephrotic syndrome (n = 35), primary glomerulonephritis (n = 15), auto-antibody associated glomerulonephritis (n = 20) and lupus nephropathy (LN, n = 15). Ten patients from the first group (29%) and 5 patients each from the second and third group (34% and 25% respectively) did not respond to MMF therapy. On the other hand, all the children diagnosed with LN have reached clinical and biochemical remission.

Conclusions

Alternative rescue MMF therapy should always be taken into consideration in proteinuric patients who are non-responders to steroids, cyclosporine A and cyclophosphamide in whom the initial glomerular filtration rate is higher than 60 ml/min/1.73m². It is recommended that MMF be administered as part of the standard treatment regimen in patients diagnosed with lupus nephropathy. In these groups of patients, the potent benefits of this therapy are higher than expected side-effects.     

Hepatitis C virus infection and locally advanced splenic marginal zone lymphoma

Splenic marginal zone lymphoma (SMZL) is a rare malignant B-cell neoplasm, usually with an indolent clinical course and favorable prognosis. Treatment options include chemotherapy, surgery, radiation and immunotherapy. In some recent studies an increased incidence of hepatitis C virus (HCV) infection in patients with SMZL was reported and its possible role in lymphomagenesis was emphasized. A 66-year-old woman with twelve-year history of HCV infection was admitted due to locally advanced abdominal tumor involving the spleen and the left part of the diaphragm. Transaminase serum levels were not elevated. Neither peripheral lymphadenopathy nor bone marrow pathology was found. Absolute blood lymphocyte, erythrocyte and platelet counts were normal. A splenectomy with partial diaphragm resection in one block was performed. Recovery was uneventful. Pathologic examination with immunohistochemistry revealed SMZL and confirmed a neoplastic infiltration of the resected diaphragm. Following surgery, chemotherapy (CHOP regimen) and immunotherapy (anti-CD20 antibody) were given. At the last follow-up 15 months after surgery, the patient was free of any symptoms of lymphoma. Surgical resection of even locally advanced SMZL with involvement of adjacent tissues can be performed as a diagnostic and therapeutic procedure. Splenectomy is especially indicated in symptomatic patients without other sites of the disease. HCV infection may result in increased risk of SMZL due to the induction of B-cell lymphoproliferation. Because of possible lymphoma regression following anti-viral therapy, a systematic screening for HCV in patients with SMZL seems to be valuable and helpful for treatment planning.