Peter K. Vogt - Böcker

Over the past 10 years, work on acute promyelocytic leukemia (APL) has become the paradigm of translational research that began with the discovery of a recurrent chromosomal translocation, followed by the identification of the genes and proteins involved, finding their molecular functions in transcriptional control, establishing mouse models and culminating in the development  of targeted therapy.

In the last few years the major effect that RNAi has had in invertebrate systems like C.elegans and drosophila is beginning to take hold in mammalian systems through both single gene knockdown experiments and genome-scale screens.

From humble beginnings over 25 years ago as a lipid kinase activity associated with certain oncoproteins, PI3K (phosphoinositide 3-kinase) has been catapulted to the forefront of drug development in cancer, immunity and thrombosis, with the first clinical trials of PI3K pathway inhibitors now in progress. Here we give a brief overview of some key discoveries in the PI3K area and their impact, and include thoughts on the current state of the field, and where it could go from here

PI3K has become a very intense area of research, with over 2000 publications on PI3K in PubMed for 2009 alone. The expectations for a therapeutic impact of intervention with PI3K activity are high, and progress in the clinical arena is being monitored by many. However, targeted therapies almost invariably encounter roadblocks, often exposing unresolved questions in the basic understanding of the target

From humble beginnings over 25 years ago as a lipid kinase activity associated with certain oncoproteins, PI3K (phosphoinositide 3-kinase) has been catapulted to the forefront of drug development in cancer, immunity and thrombosis, with the first clinical trials of PI3K pathway inhibitors now in progress. Here we give a brief overview of some key discoveries in the PI3K area and their impact, and include thoughts on the current state of the field, and where it could go from here

PI3K has become a very intense area of research, with over 2000 publications on PI3K in PubMed for 2009 alone. The expectations for a therapeutic impact of intervention with PI3K activity are high, and progress in the clinical arena is being monitored by many. However, targeted therapies almost invariably encounter roadblocks, often exposing unresolved questions in the basic understanding of the target

In the last few years the major effect that RNAi has had in invertebrate systems like C.elegans and drosophila is beginning to take hold in mammalian systems through both single gene knockdown experiments and genome-scale screens.

Regulation of gene expression at the level of transcription is one of the major determinants of proper cellular proliferation and differentiation. The key players in these processes are sequence-specific DNA binding transcription factor proteins which coordinate programs of gene expression in the nucleus. The articles in this volume document the myriad of genetic and biochemical alterations sustained by human proto-oncogenic transcription factors which result in diverse neoplastic processes. This volume gives insights into how normal programs of gene expression can be subverted by the action of single transcription factors resulting in a specific tumor type. The book provides inspiration for exploiting these tumor-specific alterations as diagnostic, prognostic tools, or as selective therapeutic targets.

More than 10 years ago, the discovery of cyclin-dependent ki­ nases (Cdks) ushered in a new era in the understanding of cell proliferation and its control. Not only were both of the known cell cycle transitions, from G 1 to S phase and G2 to M phase, found to be dependent on these protein kinases, but the reg­ ulatory assumption intrinsic to cyclin-dependent kinases, a stable inactive catalytic subunit (the Cdk) and an unstable requisite positive regulatory activating subunit (the cyclin), led to a simple model for cell cycle control. Modulation of cyclin accumulation, and thereby Cdk activation, was proposed to be the overarching principle governing the passage through cell cycle phases. An­ other reality to emerge from the discovery of Cdks was the ex­ ceptional degree of evolutionary conservation maintained in the machinery and organization of proliferation control. Not only were Cdks shown to be structurally conserved between yeast and man, but mammalian Cdks could substitute functionally for the endogenous enzymes in a yeast cell. The problem of cell cycle control was thought to have been virtually solved. The ensuing years have provided a much more complex view of cell cycle control and the role and regulation of Cdks. The uncritical enthusiasm with which many of the ideas were em­ braced has required tempering. For example, although Cdks appear to be highly conserved phylogenetically, cyclins are much less so.

Once again the Current Topics in Microbiology and Immunology series presents a volume with up-to-date review articles on oncogenes. The well-known authority and editor of previous volumes in the series, Dr. Vogt, has accepted five contributions which critically evaluate recent research in the field.

The newest volume in the Current Topics in Microbiology and Immunology series edited by Dr. Vogt and dealing with oncogenes and retroviruses contains four review articles by international authorities in the field. These articles presenting the latest research results continue the tradition of excellence for which the series is so well known.

Among the first diseases for which a viral etiology was esta- blished were tumors, lymphomas, and sarcomas in chickens, shown by Ellermann and Bang (1908) and Rous (1910) to be transmissible with cell-free filtrates. The broad significance of these discoveries was not fully recognized at first, mainly because chickens were perceived as too distanly related to humans to provide useful and relevant models for human disease. Change came slowly. In 1936 Bittner found that a viral agent is involved in the causation of mammary cancer in mice, and in 1957 Gross discovered the first murine leukemia virus. In the years following numerous tumor-inducing viruses, infecting all classes of verte- brates, were isolated. The decisive impulse for the development of the RNA tumor virus field sprang from advances in cell culture. In 1958 Temin and Rubin, following initial observations of Manaker and Groupe, worked out the conditions for virus-induced tumori- genic transformation in cell culture and made this transform- ation the basis for a quantitative assay of viral infectivity and oncogenicity.The genetic and cell biological studies that grew out of Rubin's and Temin's groundwork quickly brought into focus two puzzling problems: a requirement for DNA synthesis early in the lifecycle of the RNA tumor viruses, and the existence of genetic information in the virus that is needed for oncogenesis but not for virus reproduction.

An integrated retrovirus effectively becomes part of the cellular genome, but with the difference that the virus to a large extent retains control over its own expression through nontranslated sequences in the long terminal repeat (L TR). Some retroviruses also code for nonstructural proteins that further regulate proviral expression. Integration changes the cell genome; it adds viral genes, and in the case of transducing retroviruses also adds cell-derived oncogenes that have been incorporated into the viral genome. Integration can also have consequences for cellular genes. The transcriptional signals in a provirus can activate expression of neighboring cellular genes; the integration even can disrupt and thus inactivate cellular genes. These effects of retroviral genomes take place in cis; they are referred to as insertional mutagenesis and are the subject of this volume. Almost 10 years have passed since W. Hayward, S. Astrin, and their colleagues found that in B cell lymphomas of chickens, induced by avian leukosis virus, transcription of the cellular proto-oncogene myc was upregulated through the integration of a complete or partial provirus in its vicinity. This landmark discovery suggested a mechanism by which retro­ viruses that do not carry cellular oncogenes in their genome ("nonacute retroviruses") can cause cancer. It contributed the first evidence for the carcinogen potential of oncogenes that are not part of a viral genome.

When it comes to bacterial disease, we are living in a state of false security. Antibiotics have indeed brought unprecedented health benefits, protection from and cure of bacterial diseases during the past 50 years. But there are ominous signs that the fortress and the defenses built on antibiotics are crumbling. They are crum­ bling because we wittingly or unwittingly created selective con­ ditions for the emergence of superior pathogens that can no longer be controlled by antibiotics. There are numerous warnings. After a long period of eclipse tuberculosis has now emerged as a serious threat unchecked by antibiotic treatment. Recent years have seen reports of cholera epidemics, of anthrax infections, of serious problems with Salmonella and even with E. coli, just to name a few. Mankind is in a race with microbial invaders. The challenge is to anticipate and respond to developments that affect the precarious balance between man and microbe. This will re­ quire new knowledge and it will take time for an effective appli­ cation of that knowledge.