Duas classes de mutação na evolução de policitemia vera para leucemia mielóide aguda / Two-hit model of leukemogenesis in the evolution of polycythemia vera to acute myeloid leukemia

Policitemia vera (PV) é doença mieloproliferativa crônica com risco de transformação para mielofibrose ou para leucemia mielóide aguda (LMA) na evolução da doença. Dez a 25 por cento dos pacientes têm anormalidade citogenética ao diagnóstico, chegando a 50 por cento com a progressão. Relatamos caso de PV com transformação para LMA no qual foi possível demonstrar a teoria de duas classes de mutação: uma indutora de proliferação e outra de bloqueio de maturação. Caso: Paciente feminina, 55 anos, PV diagnosticada em 2002, com mutação JAK2V617F, cariótipo normal, tratada com flebotomias e hidroxiureia. Em 2006 houve progressão para mielofibrose pós-policitêmica e novo cariótipo mostrou 46,XX,del(20)(q13.1) em 4/20 metáfases. Análise por FISH para região 20q13 em amostra estocada confirmou a deleção ao diagnóstico. Após um ano houve transformação para LMA. A mutação JAK2V617F é suficiente para causar proliferação de precursores eritropoéticos, sendo o mecanismo fisiopatogênico primário na PV. Entretanto, a evolução da doença é heterogênea, sugerindo a ocorrência de fenômenos adicionais, levando à instabilidade genômica e contribuindo para a leucemogênese. O caso apresentado sustenta o modelo de dois passos na progressão da PV para LMA, no qual uma classe de mutação gênica confere vantagem proliferativa (JAK2V617F) e outra classe bloqueia a diferenciação hematopoética (deleção 20q). Evidenciaram-se nessa paciente dois eventos contribuindo para a proliferação e para o bloqueio de maturação. Outros mecanismos devem estar implicados e estudos prospectivos devem ser encorajados na tentativa de elucidação dos diferentes passos envolvidos na leucemogênese.

Polycythemia vera (PV) is a chronic myeloproliferative disorder that can evolve to marrow fibrosis or acute leukemia (AML). Cytogenetic alterations can be detected in around 25 percent of patients at diagnosis and in up to 50 percent of those with progression. We report a case of PV with evolution to AML in which it was possible to demonstrate the two-hit model of leukemogenesis: one mutation confers proliferative advantage and another interferes with differentiation. Case: A 55-year-old female patient was diagnosed with PV in 2002 and treated with phlebotomies and hydroxyurea. In 2006, there was progression topost-polycythemic fibrosis with AML one year later. She presented the JAK2V617F mutation. The result of karyotyping performed at diagnosis was normal and at transformation, 46,XX,del(20)(q13.1) was detected in 4/20 metaphases. FISH analysis of a stored sample for 20q13 showed the deletion in 20 percent of interphases confirming the earlier presence of a clonal abnormality that was not detected by karyotyping. The JAK2V617F mutation is sufficient to cause proliferation of hematopoietic cells and has been established as a primary pathogenetic mechanism in PV. However, the evolution of the disease is heterogeneous, suggesting the occurrence of additional phenomena contributing to leukemogenesis. This case demonstrates the two-hit model in the progression of PV to LMA, in which a class of mutation induces proliferative advantage and another blocks differentiation. Two events which contribute to proliferation and to maturation blockade were detected in this patient. Other mechanisms may be implicated and prospective studies should be encouraged in an attempt to elucidate the different steps involved in leukemogenesis.

In vivo radioprotection of mouse bone marrow: protection from apoptotic death by WR-2721

Apoptotic cell death is an important phenomenon in radiation bone marrow injury and the compound WR-2721 can protect hematopoietic tissue against such injury. In this study, we assessed the ability of WR-2721 to prevent radiation-induced apoptosis in bone marrow cells. Femoral bone marrow from C57BL male mice was used. The marrow was studied 4 h, 12 h, 24 h and 10 days after a single whole-body radiation dose of 7 Gy. Mice which received WR-2721 (400 mg/kg, i.p.) 30 min before irradiation were compared with unprotected mice. Less injury and a significant reduction in the number of apoptotic cells were observed 4 h (49.6 per cent less) and 12 h (40.8 per cent less) after irradiation in the group that received WR-2721 compared to the unprotected mice. An earlier than expected recovery was also observed 10 days after irradiation in the protected group. This is the first study in vivo to report the protection by WR-2721 of bone marrow cells from apoptosis following exposure to radiation.

Peritoneal infection by Candida albicansL study of number and size limphocytes and phagocitic activity of peritoneal macrophages in mice

The main purpose of this investigation was to study some aspects of leucocytes (granulocytes and limphocytes) and the phagocitic activity of peritoneal macrophages. In this experiment, which took place at Escola Paulista de Medicina - Universidade Federal de SÒo Paulo - Brazil, it was used twenty female C57BLACK mice. Half of them were submitted to radiation to obtain immunossupressed animals (group A - irradiated mice). The other ten mice were not irradiated (Group B - control). The animals were sorted in four subgroups: A-1, A-2, B-1 and B-2. Mice of the groups A-1 and B-1 were injected with saline, and those the subgroups A-2 and B-2, were infected with Candida albicans (ATCC 90029). The resultant data showed significant differences in the number of leucocytes (granulocytes and limphocytes), and in the medium size of limphocytes between irradiated and non irradiated mice. Related to peritoneal macrophages, it was observed that the number of macrophages was lower in irradiated mice and the phagocitic activity was decreased in the irradiated and infected animals.

Alteraçäo da fibrose hepática induzida pelo tetracloreto de carbono, pela administraçäo prévia de vitamina A

A administraçäo prévia de vitamina A a ratos em que a fibrose hepática foi induzida por injeçöes i.p. de tetracloreto de carbono resultou em significativa reduçäo dos valores de colágeno hepático e na fibrose hepática histologicamente avaliada. Os possíveis mecanismos de atuaçäo da vitamina A säo discutidos