Targeting BCR-ABL and JAK2 in Ph+ ALL.

In this issue of Blood, Appelmann et al provide evidence for prolonged survival and prevention of resistance in a mouse model of Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) by combined targeting of the BCR-ABL kinase and Janus kinase 2 (JAK2) with dasatinib and ruxolitinib, respectively.

Targeting vascular pericytes in hypoxic tumors increases lung metastasis via angiopoietin-2.

Strategies to target angiogenesis include inhibition of the vessel-stabilizing properties of vascular pericytes. Pericyte depletion in early-stage non-hypoxic tumors suppressed nascent angiogenesis, tumor growth, and lung metastasis. In contrast, pericyte depletion in advanced-stage hypoxic tumors with pre-established vasculature resulted in enhanced intra-tumoral hypoxia, decreased tumor growth, and increased lung metastasis.

Quantitative analysis and modeling probe polarity establishment in C. elegans embryos.

Cell polarity underlies many aspects of metazoan development and homeostasis, and relies notably on a set of PAR proteins located at the cell cortex. How these proteins interact in space and time remains incompletely understood. We performed a quantitative assessment of polarity establishment in one-cell stage Caenorhabditis elegans embryos by combining time-lapse microscopy and image analysis.

Pombe's thirteen - control of fission yeast cell division by the septation initiation network.

The septation initiation network (SIN) regulates aspects of cell growth and division in Schizosaccharomyces pombe and is essential for cytokinesis. Insufficient signalling results in improper assembly of the contractile ring and failure of cytokinesis, generating multinucleated cells, whereas too much SIN signalling uncouples cytokinesis from the rest of the cell cycle. SIN signalling is therefore tightly controlled to coordinate cytokinesis with chromosome segregation.

A niche role for periostin and macrophages in glioblastoma.

Macrophages facilitate tumour progression, but it is unclear whether this capability is influenced by tumour-initiating cells. Glioblastoma stem cells are now shown to secrete periostin, a matrix protein that recruits protumoral macrophages and enhances glioblastoma progression in mice.

Unexpected off-targets and paradoxical pathway activation by kinase inhibitors.

Protein kinase inhibitors are an increasingly important class of targeted anticancer therapeutics. More than two dozen new drugs of this class have entered routine clinical use over the past decade. This review article focuses on how the development of methods to study the kinome- and proteome-wide selectivity of kinase inhibitors, in conjunction with advances in the structural understanding of kinase inhibitor binding modes, has resulted in a better appreciation of the mechanism of action of clinical kinase inhibitors.

MicroRNA-206 functions as a pleiotropic modulator of cell proliferation, invasion and lymphangiogenesis in pancreatic adenocarcinoma by targeting ANXA2 and KRAS genes.

Recent advances in cancer biology have emerged important roles for microRNAs (miRNAs) in regulating tumor responses. However, their function in mediating intercellular communication within the tumor microenvironment is thus far poorly explored. Here, we found miR-206 to be abrogated in human pancreatic ductal adenocarcinoma (PDAC) specimens and cell lines.

A community computational challenge to predict the activity of pairs of compounds.

Recent therapeutic successes have renewed interest in drug combinations, but experimental screening approaches are costly and often identify only small numbers of synergistic combinations. The DREAM consortium launched an open challenge to foster the development of in silico methods to computationally rank 91 compound pairs, from the most synergistic to the most antagonistic, based on gene-expression profiles of human B cells treated with individual compounds at multiple time points and concentrations. Using scoring metrics based on experimental dose-response curves, we assessed 32 methods (31 community-generated approaches and SynGen), four of which performed significantly better than random guessing.

SAS-1 is a C2 domain protein critical for centriole integrity in C. elegans.

Centrioles are microtubule-based organelles important for the formation of cilia, flagella and centrosomes. Despite progress in understanding the underlying assembly mechanisms, how centriole integrity is ensured is incompletely understood, including in sperm cells, where such integrity is particularly critical. We identified C.

The SH2 domain of Abl kinases regulates kinase autophosphorylation by controlling activation loop accessibility.

The activity of protein kinases is regulated by multiple molecular mechanisms, and their disruption is a common driver of oncogenesis. A central and almost universal control element of protein kinase activity is the activation loop that utilizes both conformation and phosphorylation status to determine substrate access. In this study, we use recombinant Abl tyrosine kinases and conformation-specific kinase inhibitors to quantitatively analyse structural changes that occur after Abl activation.

Assessing metastasis risk after pre-operative anti-angiogenic therapy.

Anti-angiogenic drugs are approved for the treatment of several cancer types, generally in the inoperable locally advanced or metastatic setting and in combination with other anti‐cancer agents. Recent clinical studies also suggest that anti‐angiogenic drugs can be useful in the pre‐operative (neoadjuvant) setting, by facilitating the shrinkage of the primary tumour and its surgical resection. However, the effects of neoadjuvant anti‐angiogenic therapy on the ability of tumours to form distant metastases are unclear.

Genomic studies indicate a novel combination therapy for follicular lymphoma.

Follicular lymphoma (FL) is an incurable form of B-cell lymphoma. Genomic alterations that inactivate RB signaling are surprisingly common in indolent FL. We show that FLs that are positive for phosphorylated RB respond to dual CDK4/BCL2 inhibition.

The Eukaryotic Promoter Database: expansion of EPDnew and new promoter analysis tools.

We present an update of EPDNew (http://epd.vital-it.ch), a recently introduced new part of the Eukaryotic Promoter Database (EPD) which has been described in more detail in a previous NAR Database Issue.

Correlative multicolor 3D SIM and STORM microscopy.

Within the last decade, super-resolution methods that surpass the diffraction limit of light microscopy have provided invaluable insight into a variety of biological questions. Each of these approaches has inherent advantages and limitations, such that their combination is a powerful means to transform them into versatile tools for the life sciences. Here, we report the development of a combined SIM and STORM setup that maintains the optimal resolution of both methods and which is coupled to image registration to localize biological structures in 3D using multicolor labeling.

Functional characterization of the TERRA transcriptome at damaged telomeres.

Telomere deprotection occurs during tumorigenesis and aging upon telomere shortening or loss of the telomeric shelterin component TRF2. Deprotected telomeres undergo changes in chromatin structure and elicit a DNA damage response (DDR) that leads to cellular senescence. The telomeric long noncoding RNA TERRA has been implicated in modulating the structure and processing of deprotected telomeres.

Telomere functions grounding on TERRA firma.

Long noncoding telomeric repeat-containing RNAs - TERRAs - are transcribed in a regulated manner from telomeres throughout eukaryotes. TERRA molecules consist of chromosome end-specific subtelomeric sequences and telomeric repeats at their 3' ends. Recent work suggests that TERRA sustains several important functions at chromosome ends.

The shelterin component TPP1 is a binding partner and substrate for the deubiquitinating enzyme USP7.

The telomeric shelterin component TPP1 has critical functions in telomeric protein complex assembly and telomerase recruitment and regulation. Here we identify USP7 as a novel interacting protein of the oligonucleotide/oligosaccharide-binding fold of TPP1, which was previously known to recruit telomerase to telomeres. We identify amino acids in TPP1 and USP7 that are critical for their interaction and multiple lysines within TPP1 that are oligo-ubiquitinated and deubiquitinated by USP7.

Endogenous RNAs modulate microRNA sorting to exosomes and transfer to acceptor cells.

MicroRNA (miRNA) transfer via exosomes may mediate cell-to-cell communication. Interestingly, specific miRNAs are enriched in exosomes in a cell-type-dependent fashion. However, the mechanisms whereby miRNAs are sorted to exosomes and the significance of miRNA transfer to acceptor cells are unclear.

Multiciliogenesis: multicilin directs transcriptional activation of centriole formation.

During differentiation of multiciliated cells, numerous centrioles are generated in each cell to act as templates for the formation of a corresponding number of cilia. A new study reveals that multicilin, a protein required for multiciliogenesis, is a key component of a regulatory complex that activates the transcription of genes required for centriole formation.

Immunomodulatory roles of lymphatic vessels in cancer progression.

Lymphatic vessels in the tumor microenvironment are known to foster tumor metastasis in many cancers, and they can undergo activation, hyperplasia, and lymphangiogenesis in the tumor microenvironment and in the tumor-draining lymph node. The mechanism underlying this correlation was originally considered as lymphatic vessels providing a physical route for tumor cell dissemination, but recent studies have highlighted new roles of the lymphatic endothelium in regulating host immunity. These include indirectly suppressing T-cell function by secreting immunosuppressive factors and inhibiting dendritic cell (DC) maturation, as well as directly driving T-cell tolerance by antigen presentation in the presence of inhibitory ligands.

Role of angiopoietin-2 in adaptive tumor resistance to VEGF signaling blockade.

Angiopoietin-2 (ANG2/ANGPT2) is a context-dependent TIE2 receptor agonist/antagonist and proangiogenic factor. Although ANG2 neutralization improves tumor angiogenesis and growth inhibition by vascular endothelial growth factor (VEGF)-A signaling blockade, the mechanistic underpinnings of such therapeutic benefits remain poorly explored. We employed late-stage RIP1-Tag2 pancreatic neuroendocrine tumors (PNETs) and MMTV-PyMT mammary adenocarcinomas, which develop resistance to VEGF receptor 2 (VEGFR2) blockade.

Classification of selectively constrained DNA elements using feature vectors and rule-based classifiers.

Scarce work has been done in the analysis of the composition of conserved non-coding elements (CNEs) that are identified by comparisons of two or more genomes and are found to exist in all metazoan genomes. Here we present the analysis of CNEs with a methodology that takes into account word occurrence at various lengths scales in the form of feature vector representation and rule based classifiers. We implement our approach on both protein-coding exons and CNEs, originating from human, insect (Drosophila melanogaster) and worm (Caenorhabditis elegans) genomes, that are either identified in the present study or obtained from the literature.

NuMA interacts with phosphoinositides and links the mitotic spindle with the plasma membrane.

The positioning and the elongation of the mitotic spindle must be carefully regulated. In human cells, the evolutionary conserved proteins LGN/Gαi1-3 anchor the coiled-coil protein NuMA and dynein to the cell cortex during metaphase, thus ensuring proper spindle positioning. The mechanisms governing cortical localization of NuMA and dynein during anaphase remain more elusive.