Regulation of B cell linker protein transcription by PU.1 and Spi-B in murine B cell acute lymphoblastic leukemia

B cell acute lymphoblastic leukemia (B-ALL) is frequently associated with mutations or chromosomal translocations of genes encoding transcription factors. Conditional deletion of genes encoding the E26-transformation-specific transcription factors, PU.1 and Spi-B, in B cells (ΔPB mice) leads to B-ALL in mice at 100% incidence rate and with a median survival of 21 wk. We hypothesized that PU.1 and Spi-B may redundantly activate transcription of genes encoding tumor suppressors in the B cell lineage. Characterization of aging ΔPB mice showed that leukemia cells expressing IL-7R were found in enlarged thymuses. IL-7R-expressing B-ALL cells grew in culture in response to IL-7 and could be maintained as cell lines. Cultured ΔPB cells expressed reduced levels of B cell linker protein (BLNK), a known tumor suppressor gene, compared with controls. The Blnk promoter contained a predicted PU.1 and/or Spi-B binding site that was required for promoter activity and occupied by PU.1 and/or Spi-B as determined by chromatin immunoprecipitation. Restoration of BLNK expression in cultured ΔPB cells opposed IL-7-dependent proliferation and induced early apoptosis. We conclude that the tumor suppressor BLNK is a target of transcriptional activation by PU.1 and Spi-B in the B cell lineage. Copyright © 2012 by The American Association of Immunologists, Inc

Moral virtue and the principles of practical reason

This paper addresses the claim that we have a moral obligation, where a choice can be made, to bring to birth the "best" child possible. Savulescu has termed this demand the Principle of Procreative Beneficence. Thus far, a number of critical arguments have been put forward to discredit this Principle. Some focus mainly on the consequences which would follow from establishment of such an obligation, others appeal to the philosophical assumptions on which this principle is based. After a short presentation of the state of the debate over the principles of reproductive decisions, I formulate two counter-arguments which aim to demonstrate that in so far as we identify the claim that parents have some reasons to produce the best children possible and the more radical claim that they are morally obliged to attempt to do this, as biomedical decisions guidance they have little prospect of success in providing the best life possible for their children. To elucidate this problem, I turn to the ancient idea of the "good life" and to the virtue ethics with its fundamental concepts of practical wisdom and eudaimonia, which, as I argue, may provide us with a deeper understanding of what the "good life" consists in and with an explanation of what truly determines the quality of individual and one’s self-fulfillment