RESUMO
Memory B cells (MBCs) are key for protection from reinfection. However, it is mechanistically unclear how germinal center (GC) B cells differentiate into MBCs. MYC is transiently induced in cells fated for GC expansion and plasma cell (PC) formation, so-called positively selected GC B cells. We found that these cells coexpressed MYC and MIZ1 (MYC-interacting zinc-finger protein 1 [ZBTB17]). MYC and MIZ1 are transcriptional activators; however, they form a transcriptional repressor complex that represses MIZ1 target genes. Mice lacking MYC-MIZ1 complexes displayed impaired cell cycle entry of positively selected GC B cells and reduced GC B cell expansion and PC formation. Notably, absence of MYC-MIZ1 complexes in positively selected GC B cells led to a gene expression profile alike that of MBCs and increased MBC differentiation. Thus, at the GC positive selection stage, MYC-MIZ1 complexes are required for effective GC expansion and PC formation and to restrict MBC differentiation. We propose that MYC and MIZ1 form a module that regulates GC B cell fate.
Assuntos
Linfócitos B/citologia , Diferenciação Celular , Centro Germinativo/citologia , Memória Imunológica , Animais , Linfócitos B/metabolismo , Ciclo Celular/genética , Proliferação de Células/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Citidina Desaminase/metabolismo , Camundongos Knockout , Ligação Proteica , Proteínas Inibidoras de STAT Ativados/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Regulação para Cima/genéticaRESUMO
In hematopoietic malignancies, oncogenic alterations interfere with cellular differentiation and lead to tumoral development. Identification of the proteins regulating differentiation is essential to understand how they are altered in malignancies. Chronic myelogenous leukemia (CML) is a biphasic disease initiated by an alteration taking place in hematopoietic stem cells. CML progresses to a blast crisis (BC) due to a secondary differentiation block in any of the hematopoietic lineages. However, the molecular mechanisms of CML evolution to T-cell BC remain unclear. Here, we have profiled the changes in DNA methylation patterns in human samples from BC-CML, in order to identify genes whose expression is epigenetically silenced during progression to T-cell lineage-specific BC. We have found that the CpG-island of the ENGRAILED-2 (EN2) gene becomes methylated in this progression. Afterwards, we demonstrate that En2 is expressed during T-cell development in mice and humans. Finally, we further show that genetic deletion of En2 in a CML transgenic mouse model induces a T-cell lineage BC that recapitulates human disease. These results identify En2 as a new regulator of T-cell differentiation whose disruption induces a malignant T-cell fate in CML progression, and validate the strategy used to identify new developmental regulators of hematopoiesis.
Assuntos
Crise Blástica/metabolismo , Diferenciação Celular/imunologia , Regulação Neoplásica da Expressão Gênica/fisiologia , Proteínas de Homeodomínio/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Proteínas do Tecido Nervoso/metabolismo , Linfócitos T/imunologia , Animais , Ilhas de CpG/genética , Metilação de DNA/genética , Primers do DNA/genética , Progressão da Doença , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/genética , Proteínas de Homeodomínio/genética , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Camundongos , Camundongos Transgênicos , Análise em Microsséries , Proteínas do Tecido Nervoso/genética , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
The latest scientific findings in the field of cancer research are redefining our understanding of the molecular and cellular basis of the disease, moving the emphasis toward the study of the mechanisms underlying the alteration of the normal processes of cellular differentiation. The concepts best exemplifying this new vision are those of cancer stem cells and tumoral reprogramming. The study of the biology of acute lymphoblastic leukemias (ALLs) has provided seminal experimental evidence supporting these new points of view. Furthermore, in the case of B cells, it has been shown that all the stages of their normal development show a tremendous degree of plasticity, allowing them to be reprogrammed to other cellular types, either normal or leukemic. Here we revise the most recent discoveries in the fields of B-cell developmental plasticity and B-ALL research and discuss their interrelationships and their implications for our understanding of the biology of the disease.