The BMI1 polycomb protein represses cyclin G2-induced autophagy to support proliferation in chronic myeloid leukemia cells.

The BMI1 polycomb protein regulates self-renewal, proliferation and survival of cancer-initiating cells essentially through epigenetic repression of the CDKN2A tumor suppressor locus. We demonstrate here for the first time that BMI1 also prevents autophagy in chronic myeloid leukemia (CML) cell lines, to support their proliferation and clonogenic activity. Using chromatin immunoprecipitation, we identified CCNG2/cyclin G2 (CCNG2) as a direct BMI1 target. BMI1 downregulation in CD34+ CML cells by PTC-209 pharmacological treatment or shBMI1 transduction triggered CCNG2 expression and decreased clonogenic activity. Also, ectopic expression of CCNG2 in CD34+ CML cells strongly decreased their clonogenicity. CCNG2 was shown to act by disrupting the phosphatase 2A complex, which activates a PKCζ-AMPK-JNK-ERK pathway that engages autophagy. We observed that BMI1 and CCNG2 levels evolved inversely during the progression of CML towards an acute deadly phase, and therefore hypothesized that BMI1 could support acute transformation of CML through the silencing of a CCNG2-mediated tumor-suppressive autophagy response.

L-type amino-acid transporter 1 (LAT1): a therapeutic target supporting growth and survival of T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia.

The altered metabolism of cancer cells is a treasure trove to discover new antitumoral strategies. The gene (SLC7A5) encoding system L amino-acid transporter 1 (LAT1) is overexpressed in murine lymphoma cells generated via T-cell deletion of the pten tumor suppressor, and also in human T-cell acute lymphoblastic leukemia (T-ALL)/lymphoma (T-LL) cells. We show here that a potent and LAT1 selective inhibitor (JPH203) decreased leukemic cell viability and proliferation, and induced transient autophagy followed by apoptosis. JPH203 could also alter the in vivo growth of luciferase-expressing-tPTEN-/- cells xenografted into nude mice. In contrast, JPH203 was nontoxic to normal murine thymocytes and human peripheral blood lymphocytes. JPH203 interfered with constitutive activation of mTORC1 and Akt, decreased expression of c-myc and triggered an unfolded protein response mediated by the C/EBP homologous protein (CHOP) transcription factor associated with cell death. A JPH203-resistant tPTEN-/-clone appeared CHOP induction deficient. We also demonstrate that targeting LAT1 may be an efficient broad spectrum adjuvant approach to treat deadly T-cell malignancies as the molecule synergized with rapamycin, dexamethasone, doxorubicin, velcade and l-asparaginase to alter leukemic cell viability.

RET gene mutations are not involved in the origin of human testicular seminoma.

Testicular germ cell cancers are the most common solid malignancies in young men, but their pathogenesis remains undetermined although some epidemiological data have implicated both environmental and genetic factors. Glial cell-derived neurotrophic factor (GDNF) is secreted by Sertoli cells, and promotes germ stem cell proliferation by activating RET, a tyrosine kinase receptor. Over-expression of GDNF in adult transgenic mice induces the development of testicular tumours that mimic human seminoma, the most frequent testicular germ cell tumour. Activating mutations of RET were previously reported in several types of cancer, including thyroid, pituitary, adrenal and melanoma cancer. Both mouse experimental model and clinical studies suggested that mutations or selective polymorphisms of RET might be associated with human seminoma. To verify this hypothesis, we conducted this study in a French University Hospital and carried out an association study using tissue samples from 66 paraffin-embedded seminoma tumours. The most frequently mutated exons of the RET proto-oncogene were sequenced to identify mutations or selective polymorphisms. No somatic mutations were identified. The polymorphic variants frequencies did not differ from those in a control Caucasian population. Human classical seminoma that occurs in young men does not appear to be linked with mutations or relevant polymorphisms of RET.

Estrogen-induced growth inhibition of human seminoma cells expressing estrogen receptor beta and aromatase.

It is now well established that estrogens participate in the control of normal spermatogenesis and endogenous or environmental estrogens are involved in pathological germ cell proliferation including testicular germ cell tumors. Studying a human testicular seminoma cell line, JKT-1, we show here that 17beta-estradiol (10(-12) to 10(-6) M) induced in vitro a significant dose-dependent decrease of cell growth. This antiproliferative effect was maximum after 4 days of exposure at a physiologically intratesticular concentration of 10(-9) M, close to the K(d) of ER, and reversed by ICI 182780, an ER antagonist, suggesting an ER-mediated pathway. By RT-PCR and Western blot we were able to confirm that JKT-1, like tumoral seminoma cells and normal human testicular basal germ cells, expresses estrogen receptor beta (ERbeta), including ERbeta1 and ERbeta2, a dominant negative variant, but not ERalpha. Using immunofluorescence and confocal microscopy, ERbeta was observed as perinuclear intracytoplasmic spots in JKT-1 and tumoral seminoma cells without significant translocation of ERbeta into the nucleus, under 17beta-estradiol exposure. Double staining observed by confocal microscopy revealed that ERbeta colocalized in JKT-1 cells with cytochrome C, a mitochondrial marker. We report for the first time the expression of a functional aromatase complex in seminoma cells as assessed by RT-PCR, Western blot and enzymatic assay. Seminoma cells are able to respond to estrogens through a possible autocrine or paracrine loop. These preliminary results support estrogen-dependency of human testicular seminoma, the most frequent tumor of young men, and suggest potential pharmacological use. Whether this estrogen control, however, involves an ERbeta-mediated stimulation of cell apoptosis and/or an ERbeta-mediated inhibition of cell proliferation, remains to be further determined.

[Intensification of the fight against leprosy using early and systematic polychemotherapy]. / Renforcement de la lutte contre la lèpre par une polychimiothérapie précoce et systématique.

The latest epidemiologic enquiries realized in West Africa and Central Africa have shown that real prevalence of leprosy is far greater, at least twice the number of patients than are actually listed in the medical records. This data proves that the fight against leprosy is highly inefficient and stresses the partial failure of the anti-hansenian strategy that has been adopted for over 10 years in this area, in spite of the use of rifampicin in multidrug therapy which would normally cure leprosy. Therefore we suggest that the fight against leprosy should be re-organised and reinforced in high endemic areas. The anti-hansenian programmes should be carried out by specific services composed of mobile and specialised teams whose task would be to aim for the early detection and continual testing for new cases. Only with this kind of organisation can chemotherapy be administered at the beginning, therefore arresting the disease before it reaches the multi-neuritis stage. This strategy offers great epidemiologic and economic advantages and would also give hope and dignity to the patients assured of a permanent cure. Leprosy would then be classed as a disease "just like any other".

[Evaluation of endemic leprosy in an urban zone--sampling survey at the household level: results at Bamako, Republic of Mali]. / Evaluation de l'endémie lépreuse en zone urbaine--enquête par sondage au niveau des ménages: résultats à Bamako, République du Mali.

A sample survey on households was conducted in Bamako (capital of the Republic of Mali) in order to estimate epidemiological and logistical indexes relating to Hansen's disease. With a prevalence rate reaching 7.37 +/- 1.83 per thousand, a detection rate reaching 0.91 +/- 0.49 per thousand the city is a high level endemic area. All observed parameters (age, sex, racial, hygiene status, geographic distribution) seem to have no influence on disease aspect. The majority of the patients (80%) are treated by monotherapy with Dapsone, generally for excessive duration. The sociocultural impact of the Hansen's disease is very important, the physical and sensorial handicaps are frequent (34%). The survey's results could be used in order to elaborate a strategy for leprosy control based on multi-drug therapy in urban areas.

Dapsone-induced neuropathy compounds Hansen's disease nerve damage: an electrophysiological study in tuberculoid patients.

In 17 previous cases of dermatological disorders, an axonal motor neuropathy was described as a dapsone (DDS) therapy side effect. In this study, we attempted to assess DDS-induced neuropathy in the ulnar and popliteal nerves of 39 tuberculoid Hansen's disease patients using electrophysiological recordings at the time of DDS withdrawal, owing to dermatological improvement, and 4 months after. Distal motor latencies, conduction velocities at forearm and leg and above the epicondyle and the neck of the fibula were improved at a highly significant level. Twenty-five percent of the patients presented abnormal values (outside of the 95% confidence interval) at the first recording session compared to those at the second session. By contrast, parameters exploring the degree of innervation of distal muscles showed a progressive denervation. These results lead to an impairment of Hansen's disease neuropathy during DDS therapy affecting the motor conduction velocities of one quarter of the patients, and are discussed in terms of physiopathological mechanisms.

[Principle findings connected with the problems of implementing the multi-drug therapy for leprosy in West Africa]. / Principales données sur les problèmes de la mise en pratique de la polychimiothérapie de la lèpre en Afrique de l'Ouest.

The Implementation of Multidrug Therapy (MDT) in the states of West Africa oblige to analyse new restraints, in order to modify the existing health structures. The planning of Hansen's programs based on MDT needs to consider the technical and logistic parameters. Solutions are proposed for health workers training course, flow chart, drug supply system and supervision system. The advocated method uses at the existing resources, and aims at the integration into general health services, reinforced by specialized teams.

[Necrotic course of erythema nodosum leprosum]. / Erythema nodosum leprosum à évolution nécrotique.

During 2 years, 25 lepromatous patients were hospitalised in the Hansen complications room of Institut Marchoux. Between these patients, 9 developed a Necrotic Erythema Nodosum Leprosum. A review of the observed clinic effects is established and 3 types of signs are isolated and discussed: necrotic extension after big nodes on chest and arms, a punch crater complicating small nodes, and a sclerous xylodermia on arms and legs. The course of this complication is estimated about six months average, with pauses and relapses with general and subjectives symptoms. The final course shows side effects: anemia, denutrition, functional disabilities of joint movements and cutaneous straps. In the group of 9 patients, 3 died. We did not find relations between the necrotic phenomenon and therapy or occurred diseases. The best drug to stop the necrotic processus is thalidomide 400 mg daily and decrease 100 mg when the signs fall near normality. One or two mg/kg each day coricosteroides were tested: the effect is unconstant, the duration of action is shorter. Side effects occur rapidly and patient will become corticosteroïd dependent. The importance of bath with disinfectants is high. We did not observed surinfection.

[Integration of leprosy polychemotherapy into general health services]. / Intégration de la polychimiothérapie anti-hansénienne dans les structures collectives de santé.

The actual control of leprosy must conciliate difficulties of multidrug therapy (MDT) application and integration of general health services. The getting up of multidrug therapy needs a logistic with clinical and bacteriological track off, patient categorisation, supervision of treatment, follow up of the drug compliance and control of the disease evolution. The management of such system must be perfectly mastered in order to avoid the uncontroled circulation of rifampicine. Solutions are proposed in order to increase specialized teams efficiency and integration of non specialized officers incumbent tasks.

[Results of animal experimentation activities at the Institut Marchoux in Bamako (1982-1984)]. / Bilan d'activité de l'animalerie expérimentale de l'Institut Marchoux de Bamako (1982-1984).

The Institut Marchoux animal research unit report of activities 1982-1984 shows increasing results in mouse-foods-pads inoculations. Among 17 multibacillary cases, 16 were clinically dapsone-resistant suspected. In 9 cases there was no multiplication; however in 4 cases, multiplication were observed in the untreated controled mice group but no multiplication in dapsone groups. Three cases were fully dapsone-resistant in all concentrations tested. In one case we have detected a partial DDS resistance. No multiplication in the mice group with 10(-2) dapsone dict, but multiplication in 10(-3) and 10(-4) dapsone dict.

[Present-day difficulties in the campaign against leprosy and proposals for its resumption in French-speaking Africa]. / Difficultés actuelles de la lutte contre la lèpre et propositions de relance en Afrique francophone.

Until recent years the control of leprosy lied over a semi-specific organisation called "lutte contre les Grandes Endémies". Their strategy was based on the facilities of specialists teams practicing systematic medical visits ware the track-down, the treatment by monotherapy and the annual control of the patients. With appearance of social and economic difficulties the activity of these services has greatly decreased and the control of leprosy has known a stop in many countries. Also this organisation is no long a fit to the use of new regimens based on multitherapy. Solutions are proposed having in mind the objectives to follow scientific and logistic demands all the facilities. Summary all the facilities should be used without exception and without hesitation: lights move-over teams, fixed centers, educationals facilities, etc... This combination of this facilities and the wish to fight by the population and the health personals could only assure the success of new programs against leprosy.