RESUMO
In human B-acute lymphoblastic leukemia (B-ALL), RAG1-induced genomic alterations are important for disease progression. However, given that biallelic loss of the RAG1 locus is observed in a subset of cases, RAG1's role in the development of B-ALL remains unclear. We chose a p19Arf(-/-)Rag1(-/-) mouse model to confirm the previously published results concerning the contribution of CDKN2A (p19ARF /INK4a) and RAG1 copy number alterations in precursor B cells to the initiation and/or progression to B-acute lymphoblastic leukemia (B-ALL). In this murine model, we identified a new, Rag1-independent leukemia-initiating mechanism originating from a Sca1(+)CD19(+) precursor cell population and showed that Notch1 expression accelerates the cells' self-renewal capacity in vitro. In human RAG1-deficient BM, a similar CD34(+)CD19(+) population expressed p19ARF. These findings suggest that combined loss of p19Arf and Rag1 results in B-cell precursor leukemia in mice and may contribute to the progression of precursor B-ALL in humans.
Assuntos
Linfócitos B/fisiologia , Inibidor p16 de Quinase Dependente de Ciclina/genética , Células-Tronco Hematopoéticas/fisiologia , Proteínas de Homeodomínio/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Animais , Antígenos CD19/metabolismo , Antígenos CD34/metabolismo , Antígenos Ly/metabolismo , Apoptose/fisiologia , Linfócitos B/metabolismo , Linfócitos B/patologia , Células da Medula Óssea/citologia , Células da Medula Óssea/fisiologia , Células Cultivadas , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Regulação Leucêmica da Expressão Gênica/fisiologia , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Proteínas de Homeodomínio/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Mutantes , Transplante de Neoplasias , Fenótipo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Receptor Notch1/genética , Transdução de Sinais/fisiologia , Células Estromais/citologia , Células Estromais/fisiologiaRESUMO
BACKGROUND: Chromatoid bodies (CBs) are characteristic spermatid organelles, which were suggested to function in RNA storage and small RNA processing but whose functions remain largely unknown. CB components include Mili, Miwi, and Tudor domain proteins such as Tdrd6, whose contribution to CB structure and function is elusive. RESULTS: We determined gametogenesis stage- and male-specific expression and localization of Tdrd6, identified a C-terminally truncated form as predominant after meiosis I, and demonstrated direct physical interaction of Tdrd6 with the CB components Mili and Miwi. Development from round into elongated spermatids is abrogated in Tdrd6(-/-) mice. Their round spermatids bear "ghost" CBs, whose architecture is greatly disrupted. Mael, Miwi, and Mvh do not localize to the Tdrd6-deficient CBs, but retrotransposons are not significantly activated. However, more than 50 miRNAs are more abundant in Tdrd6(-/-) testes, as are exemplary pre- and pri-miRNAs. CONCLUSION: We conclude that Tdrd6 is essential for spermiogenesis, for CB structure, and for proper mature and precursor miRNA expression.