Successful Nilotinib Treatment in a Child with Chronic Myeloid Leukemia

A 16-year-old female was diagnosed incedentally with chronic myeloid leukemia (CML) in the chronic phase. She showed complete remission after 3 months of nilotinib treatment. CML is a rare malignant neoplasm in pediatric age. It is characterized by a Philadelphia chromosome, which comes from a genetic translocation between chromosomes 9 and 22. This translocation results in an abnormal fusion called BCR-ABL oncogene which encodes a chimeric BCR-ABL protein. This protein is the underlying cause of CML. Nilotinib is a newly licensed drug for CML in adults. Structurally, it is similar to imatinib (the older tyrosine kinase inhibitor), but it is much more potent in inhibiting BCR-ABL due to its much increased affinity for its binding site. Specific guidelines for CML treatment in children have yet to be determined. In our patient, nilotinib was used as an off-label drug because it is not licensed for children. According to the pharmacokinetic response to drugs, children cannot be considered small adults irrespective of their weight. Off-label drug use based on evidence that it is the best treatment available is an important tool in the hands of expert treating physicians.

HELICOBACTER PYLORI AND t(11;18)(q21;q21) TRANSLOCATION IN GASTRIC MALT LYMPHOMA

ContextGastric mucosa-associated lymphoid tissue (MALT) lymphoma is clearly associated with Helicobacter pylori gastritis and can be cured with anti- H pylori therapy alone. The presence of t(11;18)(q21;q21) translocation is thought to predict a lower response rate to anti- H pylori treatment.ObjectivesTo study the presence of t(11;18)(q21;q21) genetic translocation and its clinical impact in low-grade gastric MALT lymphoma Brazilian patients.MethodsA consecutive series of eight patients with gastric MALT lymphoma were submitted to gastroscopy, endoscopic ultrasound, histopathological examination, H pylori search and RT-PCR-based methodology. All patients received anti-H pylori treatment. Eradicated patients were followed-up every 3-6 months for 2 years.ResultsEight patients were studied. All patients had tumor involvement restricted to the mucosa or submucosa and seven patients had low-grade gastric MALT lymphoma. All infected patients achieved H pylori eradication. Histological tumor regression was observed in 5/7 (71%) of the low-grade gastric MALT lymphoma patients. The presence of t(11;18)(q21;q21) translocation was found in 4 (57%) of these patients; among them only two had histological tumor regression following H pylori eradication.ConclusionsRT-PCR is a feasible and efficient method to detect t(11;18)(q21;q21) translocation, being carried out in routine molecular biology laboratories. The early detection of such translocation can be very helpful for better targeting the therapy to be applied to gastric MALT lymphoma patients.

Alveolar Soft Part Sarcomas: Molecular Pathogenesis and Implications for Novel Targeted Therapies

Alveolar soft part sarcoma (ASPS) is a very rare soft tissue sarcoma which arises primarily in children and young adults. Despite its unique histology and well-characterized genetic translocation, many questions remain regarding the pathogenesis and treatment of this tumor type. Though collective clinical experience with this tumor type spans more than 60 years, there has been little progress made in treating this uncommon but frequently fatal disease. This paper focuses on the available data regarding its molecular pathogenesis and insights into targeted therapeutics as well as the results of clinical trials performed to date to hopefully improve the outcome of patients with this rare malignancy.

DNA Methylation Analysis of 807 Genes in Chronic Myeloid Leukemia and Acute Promyelocytic Leukemia.

DNA methylation changes are a common finding in leukemia, and hypermethylation of CpG island promoters is associated with aberrant gene silencing. Some abnormal cancer related methylation changes have been associated with clinical phenotype including pathologic features, prognosis, and treatment response. However, other DNA methylation changes do not appear to have phenotypic consequences and may reflect a stochastic event or a downstream event of tumorogenesis, such as the CpG island methylator phenotype (CIMP). In order to obtain a better understanding of the DNA methylation changes found in leukemia we analyzed 18 acute promyelocytic leukemia (APL) and 36 chronic myeloid leukemia (CML) patients. We specifically chose to study APL and CML as these leukemia are initiated by specific genetic translocation events, t(15:17) and t(9:22) respectively. To measure the DNA methylation status, we used the GoldenGate Assay for Methylation and BeadArray technology from Illumina, Inc. The Standard Methylation Cancer Panel I from Illumina interrogates 1505 CpG sites, selected from 807 genes (231 genes contain one CpG site per gene, 463 genes contain two CpG sites and 114 genes have three or more CpG sites). In our study we found 142 and 269 genes that were hypermethylated in CML and APL. 31 genes were uniquely hypermethylated in CML, 158 genes were hypermethylated only in APL, and 111 genes were hypermethylated in both leukemias. There was a unique pattern of hypermethylated genes in each cancer; such there was a high concordance of hypermethylated genes within each leukemia type. These data suggest that the epigenetic events were a result of the genetic translocation BCR/ABL or PML/RARα (associated with chromosomal aberrations t(9:22) or t(15:17)) that initiates these leukemias. Analysis of the number of hypermethylated genes in these two leukemias showed a bimodal distribution suggestive of CIMP, however, closer examination showed that this bimodal distribution could be attributed to the two different types of leukemia. APL patients had mean of 280 genes hypermethylated while CML patients only had a mean of 193 genes hypermethylated. APL had a stronger methylator phenotype than CML for the loci studied, which underscores the possible relationship of CIMP to a genetic phenotype. Subset analysis of our CML samples by chronic phase (23 patients), accelerated phase (5 patients), and blast crisis (8 patients) revealed 42 genes that became hypermethylated with progression of CML. It is possible that hypermethylation of these genes are clinically important in the leukemia phenotype, and maybe targets for epigenetic therapy. We examined the DNA methylation changes induced by the DNA methylation inhibitor, azacitidine, in a patient with blast crisis CML and refractory to imatinib mesylate therapy. Azacitidine could reverse the aberrant hypermethylation associated with progression of CML to blast crisis and supports the use of this drug as an epigenetic therapy. Our data show that the majority of DNA hypermethylation events in leukemia are dependent on genetic events, but there is a subset of DNA hypermethylation events that are involved in the progression of leukemia and may be therapeutically reversed by DNA methylation inhibitors.

The Role of Translocation and Selection in the Emergence of Genetic Clusters and Modules

Biomolecular studies point increasingly to the importance of modularity in the organization of the genome. Processes such as the maintenance of metabolism are controlled by suites of genes that act as distinct, self-contained units, or modules. One effect is to promote stability of inherited characters. Despite the obvious importance of genetic modules, the mechanisms by which they form and persist are not understood. One clue is that functionally related genes tend to cluster together. Here we show that genetic translocation, recombination, and natural selection play a central role in this process. We distill the question of emerging genetic modularity into three simulation experiments that show: (1) a tendency, under natural selection, for essential genes to co-locate on the same chromosome and to settle in fixed loci; (2) that genes associated with a particular function tend to form functional clusters; and (3) that genes within a functional cluster tend to become arranged in transcription order. The results also imply that high proportions of junk DNA are essential to the process.