Inhibition of autophagy enhances apoptosis induced by bortezomib in AML cells

Bortezomib is a novel proteasome inhibitor, which has been successfully used to treat mantle cell lymphoma and multiple myeloma. However, the direct effects of bortezomib on acute promyelocytic leukaemia (APL) have not been fully investigated. In the present study, the WST-8 assay, western blotting, flow cytometry, monodansylcadaverine staining and transmission electron microscopy were performed. It was demonstrated that bortezomib treatment induced a time- and dose-dependent decrease in the viability of NB4 cells. Bortezomib treatment induced cell apoptosis in NB4 cells, as assessed by Annexin V/propidium iodide analysis, and the detection of cleaved caspase-3, cleaved poly(ADP-ribose) polymerase, Bax and Bcl-2 expression. Furthermore, bortezomib treatment induced autophagy in NB4 cells, as indicated by autophagosome formation, p62 degradation, LC3-I to LC3-II conversion and formation of acidic autophagic vacuoles. Notably, autophagy induced by bortezomib was initiated prior to apoptosis. Inhibition of autophagy by knocking down Beclin-1 expression increased bortezomib-induced apoptosis in NB4 cells. Therefore, the present study revealed that the combination of bortezomib and autophagy inhibition may be a potential treatment strategy for APL.     

Debut y manejo de leucemia mieloblástica aguda durante la gestación: a propósito de un caso

Acute myeloid leukaemia (AML) is one of the deadliest haematological malignancies. During pregnancy it is a rare comorbidity and can lead to adverse outcomes, such as death, without adequate treatment. The management of AML during pregnancy remains a challenge. We report the case of a primigravida 34-year-old, with 18 weeks of amenorrhoea, who attended the emergency department presenting with pain and hypertrophy of the oral mucosa, accompanied by intense asthenia. Acute myeloblastic leukaemia was diagnosed. The possibility of terminating the pregnancy was offered given the lack of evidence regarding the maternal-foetal outcome, but the patient rejected it, so chemotherapy treatment was started. In the ultrasound controls there was no evidence of teratogenic alterations nor foetal growth restriction, and there were no alterations in Doppler flow values. It was decided to end the pregnancy at 32 + 3 GW. A preterm male was born through eutocic delivery with a normal Apgar test and umbilical cord pH, and did not require resuscitation. The puerperium was favourable and 15 days following discharge she was admitted for a bone marrow transplant from her HLA identical sister. The patient died due to rejection of the transplant and the complications derived from this event.     

Acute leukaemia in a defined geographic area – Incidence,clinical history and prognosis

A consecutive series of patients (1978–1981) comprising all patients with acute leukaemia from a population of 475000 inhabitants was reviewed. Thus, 94 patients were diagnosed as having acute leukaemia. No patients were lost from follow-up. The incidence figures of ALL and AML differed significantly from those of Sweden as a whole. 9 patients were < 15 years old. The median age of adult patients was 64 years, 60.8% being ≥ 60 years old. Of adult patients with AML, 20% had a preleukaemic history (chronic myeloproliferative disorders, myelodysplastic syndromes and others). None of 6 patients with leukaemia as a metamorphosis of a chronic myeloproliferative disorder achieved a complete remission. The overall remission rate of the remaining adult patients was 25%. Treated patients, 15–39 years old, with AML without any preleukaemic history, had a complete remission rate of 80% compared to 12% for patients ≥ 60 years old with the same diagnosis. Of 60 patients with ‘primary’ AML, 14 were not treated, mainly because of advanced age and complicating diseases. Most of these patients died within a week of admission.     

Chronic lymphocytic leukaemia and lymphoma in an Iranian fat-tailed sheep: a case report

A 5-year-old Iranian fat-tailed sheep was referred to the Veterinary Clinic of Shiraz University in September 2003 with a history of emaciation, fever, decreased appetite, lethargy and cough. Small cutaneous and subcutaneous nodules were palpable, especially under the ribs on both sides of the thorax. Discrete cutaneous plaques and large scabby lesions were also observed. Very large mammary gland lymph nodes were noticed on palpation. Haematological and serum biochemical values were estimated through standard haematological and biochemical techniques. In this case a normocytic–normochromic anaemia, leukocytosis and lymphocytosis were found. The concentrations of blood urea nitrogen (BUN), creatinine, cholesterol and the activities of aspartate aminotransferase (AST) and gamma-glutamyl transferase (GGT) were higher than the values reported for sheep. Necropsy findings revealed that the lymph nodes were affected in most organs. Malignant lymphoma in the kidney, heart, spleen, mammary glands, liver and bone marrow was observed. The histopathological appearance of the affected tissues varied considerably, depending upon the degree of tumour infiltration. According to the history, clinical signs, laboratory findings, necropsy findings and histopathological examination the case was diagnosed as chronic lymphocytic leukaemia and lymphoma.     

Trisomy 8 in acute promyelocytic leukaemia: an interphase study by fluorescence in situ hybridization

Summary. Acute promyelocytic leukaemia (APL) is characterized by t(15;17)(q24;q21). Trisomy 8 is the commonest accompanying karyotypic aberration. We investigated 14 APL patients for trisomy 8 using fluorescence in situ hybridization (FISH). Conventional cytogenetic analysis showed trisomy 8 in two of nine successfully karyotyped cases. With FISH, a possible third case showing a subclone (1-2-5%) with trisomy 8 was found. The trisomy 8 clone size defined by karyotyping and FISH was concordant in one case and discordant in another, in which trisomy 8 was found in 100% of metaphases but only in 48% of leukaemic prbmyelocytes by FISH. Therefore trisomy 8 was mosaic in all the cases, suggesting that it had arisen from clonal evolution. AU-trans-retinoic acid successfully induced morphologic remission in both cases with trisomy 8.     

A long-term time course of colorimetric assessment of the effects of imatinib mesylate on skin pigmentation: a study of five patients

BACKGROUND: Imatinib mesylate (IM), the first-line treatment of chronic myeloid leukaemia (CML), is a tyrosine kinase inhibitor that targets those proteins involved in BCR-ABL signal transduction in CML, c-kit (KIT) and platelet-derived growth-factor (PDGFR) receptor. The use of IM has been associated with cutaneous reactions. In the last 2 years numerous studies have focused the attention on hypopigmentations, depigmentations and photosensitivity developing after the initiation of IM therapy. OBJECTIVE: The aim of this study is to evaluate the effects of IM therapy on the skin pigmentation of five patients affected by CML. METHODS: Skin pigmentation measurements were performed with a Minolta CR-200 Chromameter. results: All the studied patients show the gradual lightening of the skin on unexposed areas over the treatment with IM. In particular, this explorative colorimetric study indicates the association between IM and skin depigmentation with a significant increase of luminance value (L*) (P = 0.001) and a significant decrease of the pigmentation value (b*) (P = 0.028). CONCLUSION: Even if we do not know the clinical significance of the skin depigmentation caused by IM, the regulatory role of KIT and its ligand stem cell factor in melanocyte development and survival seems to suggest an objective mechanism of action for IM in the pathogenesis of this cutaneous depigmentation.