MLL amplification in myeloid leukemias: A study of 14 cases with multiple copies of 11q23

We here report the clinical, cytogenetic, fluorescence in situ hybridization (FISH), and Southern blot data on 14 patients with a myeloid malignancy and structural aberration of chromosome band 11q23 associated with overrepresentation or amplification of the MLL gene. The number of copies of MLL varied from three (two cases) to a cluster consisting of multiple hybridization spots. Together with previous reports, available data indicate that amplification of 11q23/MLL is a recurrent genetic change in myeloid malignancy. It affects mainly elderly patients and is often associated with dysplastic bone marrow changes or with complex karyotypic aberrations, suggestive of genotoxic exposure. It is associated with a poor prognosis. In addition, FISH analysis of nine cases with additional 11q probes showed that the overrepresented chromosomal region is generally not restricted to MLL, and Southern blot analysis indicated that amplification does not involve a rearranged copy of this gene. The significance of MLL amplification and the mechanisms by which it could play a role in leukemogenesis and/or disease progression remain to be elucidated.     

Melatonin antagonizes the intrinsic pathway of apoptosis via mitochondrial targeting of Bcl-2

Abstract:  We have recently shown that melatonin antagonizes damage-induced apoptosis by interaction with the MT-1/MT-2 plasma membrane receptors. Here, we show that melatonin interferes with the intrinsic pathway of apoptosis at the mitochondrial level. In response to an apoptogenic stimulus, melatonin allows mitochondrial translocation of the pro-apoptotic protein Bax, but it impairs its activation/dimerization The downstream apoptotic events, i.e. cytochrome c release, caspase 9 and 3 activation and nuclear vesiculation are equally impaired, indicating that melatonin interferes with Bax activation within mitochondria. Interestingly, we found that melatonin induces a strong re-localization of Bcl-2, the main Bax antagonist to mitochondria, suggesting that Bax activation may in fact be antagonized by Bcl-2 at the mitochondrial level. Indeed, we inhibit the melatonin anti-apoptotic effect (i) by silencing Bcl-2 with small interfering RNAs, or with small-molecular inhibitors targeted at the BH3 binding pocket in Bcl-2 (i.e. the one interacting with Bax); and (ii) by inhibiting melatonin-induced Bcl-2 mitochondrial re-localization with the MT1/MT2 receptor antagonist luzindole. This evidence provides a mechanism that may explain how melatonin through interaction with the MT1/MT2 receptors, elicits a pathway that interferes with the Bcl-2 family, thus modulating the cell life/death balance.     

Biosimilaires actuellement disponibles en hémato-oncologie Partie I: ASEs (agents stimulant l’érythropoïèse)

The understanding of control mechanisms in the production of erythrocytes has been advanced by the discovery of erythropoietin and by the cloning of its gene. This has allowed commercial development of human recombinant erythropoietin (rHuEPO). The usage of erythropoiesis-stimulating agents (ESAs) is important in treating anemia in patients with chronic renal failure, in patients suffering from neoplastic diseases with chemotherapy-induced anemia, as well as in some myelodysplastic syndromes. After several years of questions, controversies and discussions, the respective indications for the usage of ESA, i–v iron and blood transfusions seem to settle down in chemotherapy-induced anemia. A new issue is coming up now: where and how do ESA biosimilars fit in?     

Nouveaux anticoagulants : ont-ils déjà une place en oncologie ?

Since 2008, novel oral anticoagulants have become available, initially in postoperative orthopaedics and then in cardiology as preventive treatment for thrombophilia in non-valvular atrial fibrillation. Recently, the indication of rivaroxaban has been extended to include deep vein thrombosis and pulmonary embolism, with cancer patients also being included. The advantage of these products centres on the fact that they are administered orally and, as opposed to vitamin K antagonists, laboratory testing is not required. Furthermore, there are also substantially fewer interactions with other medicinal products and certain foods. It has been found that there is no antidote available for these products and that they are eliminated via the kidneys; renal failure is therefore a restrictive factor in their use. Various trials have shown potential haemorrhagic complications, as with othermedicinal products; therefore informing the patient is vital and each patient should receive documentation required by the regulatory authorities and provided by the laboratories. Within the area of heparins, numerous novel products known as “ultra-low molecular weight heparins” are being investigated and several trials have been presented and published, including the use of semuloparin as a preventive treatment. These products are yet to be commercialised, so it is still too early to speculate on their future position as treatment options.     

Anemia in cancer: some pathophysiological aspects

More than 30% of cancer patients experience anemia and its side effect, fatigue. Its causes can be numerous, but anemia is usually secondary to an imbalance of cytokines. Among these, tumor necrosis factor-alpha seems to be the major culprit, creating anemia by blunting the physiological effect of erythropoietin. Pharmacologically increasing the erythropoietin level corrects the anemia in about half the treated patients. Several studies have shown that quality of life is substantially improved through such therapy.     

Comparison of standard PCR and the LightCycler technique to determine the thrombophilic mutations: an efficiency and cost study.

For several years it has been possible to routinely detect numerous mutations in the human genome by different methods. The most common technique is a standard PCR, but real time fluorescence PCR is increasingly being used. The purpose of this paper is to compare these two different techniques from the point of view of reliability, time consumption, and cost. More than 600 DNA samples of prevalence studies and from cancer patients were used to determine mutations in the genes of coagulation factor V Leiden, prothrombin, and methylenetetrahydrofolate reductase using standard PCR. A subset of 132 samples from the same pool was also tested by LightCycler PCR for the same coagulation gene mutations. Originally LightCycler techniques were applied for quantitative PCR by real time fluorescence measuring. Adding a melting curve analysis allows mutation detection. The results were perfectly concordant. The cost for the reagents is nearly the same for both methods but the time consumption for standard PCR is much higher than for the LightCycler method, resulting in higher laboratory personnel costs.