IntroductionIf we are to exploit biologic insights for new therapies of hematologic malignancies, it is important to consider 2 distinct features of the target tumor: (1) the developmental process, by which a normal cell becomes transformed into an established tumor; and (2) the susceptibility or resistance of the malignant cells to current therapies. Most investigators do not separate these 2 features, focusing only on the link between the particular aspect being studied and clinical outcome. For example, in B-cell lymphoma, gene expression profiles have been used to predict survival, an outcome more likely to be determined by susceptibility to treatment than by the pathogenic process. 1 In many cases, this restricted view is inevitable because hematologic malignancies are often treated quite quickly, making the connection between cellular features and the natural history of the tumor difficult to analyze.Among B-cell malignancies, chronic lymphocytic leukemia (CLL) is a shining exception because its relatively indolent nature enables detailed investigation of tumor cells, often in the absence of treatment, as well as observation of tumor behavior over time. This window of opportunity has facilitated the identification of prognostic factors that relate to pathogenesis. It is even possible now to detect minor clonal expansions, defined as monoclonal B-cell lymphocytoses, in ϳ 3% of healthy persons, potentially revealing the very early stages of CLL. 2 In CLL, there is the added advantage of availability of tumor cells from blood, although conclusions based on this compartment have to be tempered by the fact that critical proliferative events occur in tissue sites.There is now strong evidence that signaling via the B-cell receptor (BCR) plays a major role in the development of CLL and that it determines the variable clinical behavior. In this Perspective, we discuss the functional significance of the BCR in CLL and we describe strategies to target BCR signaling as a new therapeutic approach. Insights into pathogenesis from the expressed IgB-cell malignancies offer a major advantage to investigators, in that the immunoglobulin (Ig) component of the BCR has unique molecular features that mark the tumor cell and reveal the nature of the B cell of origin. 3 Most cases of CLL express IgM and IgD, and it is now clear that the disease can be divided into 2 main subsets, based on whether the tumor arose from a B cell before initiation of somatic hypermutation in Ig variable (V) region genes (unmutated [U] CLL) or after this process had taken place and then stopped (mutated [M] CLL). The rather dramatic difference in tumor behavior, with U-CLL being generally more aggressive than M-CLL, 4,5 was unexpected, although perhaps it should not have been, given the clinical differences between other B-cell tumor categories.In CLL, the Ig expressed at the cell surface is rarely lost, indicating an essential influence on the tumor cell. Because the IGHVHDHJ and IGLVLJ sequences, and the isotype, reflect the normal counterpart, it i...

The Salvador/Warts/Hippo (Hippo) signaling pathway defines a novel signaling cascade regulating cell contact inhibition, organ size control, cell growth, proliferation, apoptosis and cancer development in mammals. The upstream regulation of this pathway has been less well defined than the core kinase cassette. KIBRA has been shown to function as an upstream member of the Hippo pathway by influencing the phosphorylation of LATS and YAP, but functional consequences of these biochemical changes have not been previously addressed. We show that in MCF10A cells, loss of KIBRA expression displays epithelial-to-mesenchymal transition (EMT) features, which are concomitant with decreased LATS and YAP phosphorylation, but not MST1/2. In addition, ectopic KIBRA expression antagonizes YAP via the serine 127 phosphorylation site and we show that KIBRA, Willin and Merlin differentially regulate genes controlled by YAP. Finally, reduced KIBRA expression in primary breast cancer specimens correlates with the recently described claudin-low subtype, an aggressive sub-group with EMT features and a poor prognosis.

Idiopathic pulmonary fibrosis (IPF), the prototypic progressive fibrotic interstitial lung disease, is thought to be a consequence of repetitive micro-injuries to an ageing, susceptible alveolar epithelium. Ageing is a risk factor for IPF and incidence has been demonstrated to increase with age. Decreased (macro)autophagy with age has been reported extensively in a variety of systems and diseases, including IPF. However, it is undetermined whether the role of faulty autophagy is causal or coincidental in the context of IPF. Here, we report that in alveolar epithelial cells inhibition of autophagy promotes epithelial-mesenchymal transition (EMT), a process implicated in embryonic development, wound healing, cancer metastasis and fibrosis. We further demonstrate that this is attained, at least in part, by increased p62/SQSTM1 expression that promotes p65/RELA mediated-transactivation of an EMT transcription factor, Snail2 (SNAI2), which not only controls EMT but also regulates the production of locally acting profibrogenic mediators. Our data suggest that reduced autophagy induces EMT of alveolar epithelial cells and can contribute to fibrosis via aberrant epithelial-fibroblast crosstalk.