Activity of immunoproteasome inhibitor ONX-0914 in acute lymphoblastic leukemia expressing MLL-AF4 fusion protein.

Proteasome inhibitors bortezomib and carfilzomib are approved for the treatment of multiple myeloma and mantle cell lymphoma and have demonstrated clinical efficacy for the treatment of acute lymphoblastic leukemia (ALL). The t(4;11)(q21;q23) chromosomal translocation that leads to the expression of MLL-AF4 fusion protein and confers a poor prognosis, is the major cause of infant ALL. This translocation sensitizes tumor cells to proteasome inhibitors, but toxicities of bortezomib and carfilzomib may limit their use in pediatric patients.

Characterizing the heterogeneity in 5-aminolevulinic acid-induced fluorescence in glioblastoma.

Objective: 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX) fluorescence is an effective surgical adjunct for the intraoperative identification of tumor tissue during resection of high-grade gliomas. The use of 5-ALA-induced PpIX fluorescence in glioblastoma (GBM) has been shown to double the extent of gross-total resection and 6-month progression-free survival. The heterogeneity of 5-ALA-induced PpIX fluorescence observed during surgery presents a technical and diagnostic challenge when utilizing this tool intraoperatively.

Glioma Cell Secretion: A Driver of Tumor Progression and a Potential Therapeutic Target.

Cellular secretion is an important mediator of cancer progression. Secreted molecules in glioma are key components of complex autocrine and paracrine pathways that mediate multiple oncogenic pathologies. In this review, we describe tumor cell secretion in high-grade glioma and highlight potential novel therapeutic opportunities.

A recombinant lentiviral PDGF-driven mouse model of proneural glioblastoma.

Background: Mouse models of glioblastoma (GBM), the most aggressive primary brain tumor, are critical for understanding GBM pathology and can contribute to the preclinical evaluation of therapeutic agents. Platelet-derived growth factor (PDGF) signaling has been implicated in the development and pathogenesis of GBM, specifically the proneural subtype. Although multiple mouse models of PDGF-driven glioma have been described, they require transgenic mice engineered to activate PDGF signaling and/or impair tumor suppressor genes and typically represent lower-grade glioma.

ID2 promotes survival of glioblastoma cells during metabolic stress by regulating mitochondrial function.

Tumor cells proliferate in cellular environments characterized by a lack of optimal tissue organization resulting oftentimes in compromised cellular metabolism affecting nutrition, respiration, and energetics. The response of tumor cells to adverse environmental conditions is a key feature affecting their pathogenicity. We found that inhibitor of DNA binding 2 (ID2) expression levels significantly correlate with the ability of glioblastoma (GBM)-derived cell lines to survive glucose deprivation.

Pediatric Brain Tumors: Current Knowledge and Therapeutic Opportunities.

Great progress has been made in many areas of pediatric oncology. However, tumors of the central nervous system (CNS) remain a significant challenge. A recent explosion of data has led to an opportunity to understand better the molecular basis of these diseases and is already providing a foundation for the pursuit of rationally chosen therapeutics targeting relevant molecular pathways.

PDGF Engages an E2F-USP1 Signaling Pathway to Support ID2-Mediated Survival of Proneural Glioma Cells.

Glioblastoma is the most aggressive primary brain tumor and responds poorly to currently available therapies. Transcriptomic characterization of glioblastoma has identified distinct molecular subtypes of glioblastoma. Gain-of-function alterations leading to enhanced platelet-derived growth factor (PDGF) signaling are commonly observed in the proneural subtype of glioblastoma and can drive gliomagenesis.

Id2 mediates oligodendrocyte precursor cell maturation arrest and is tumorigenic in a PDGF-rich microenvironment.

Maturation defects occurring in adult tissue progenitor cells have the potential to contribute to tumor development; however, there is little experimental evidence implicating this cellular mechanism in the pathogenesis of solid tumors. Inhibitor of DNA-binding 2 (Id2) is a transcription factor known to regulate the proliferation and differentiation of primitive stem and progenitor cells. Id2 is derepressed in adult tissue neural stem cells (NSC) lacking the tumor suppressor Tp53 and modulates their proliferation.

Serine/threonine kinase 17A is a novel candidate for therapeutic targeting in glioblastoma.

STK17A is a relatively uncharacterized member of the death-associated protein family of serine/threonine kinases which have previously been associated with cell death and apoptosis. Our prior work established that STK17A is a novel p53 target gene that is induced by a variety of DNA damaging agents in a p53-dependent manner. In this study we have uncovered an additional, unanticipated role for STK17A as a candidate promoter of cell proliferation and survival in glioblastoma (GBM).

Elevated Id2 expression results in precocious neural stem cell depletion and abnormal brain development.

Id2 is a helix-loop-helix transcription factor essential for normal development, and its expression is dysregulated in many human neurological conditions. Although it is speculated that elevated Id2 levels contribute to the pathogenesis of these disorders, it is unknown whether dysregulated Id2 expression is sufficient to perturb normal brain development or function. Here, we show that mice with elevated Id2 expression during embryonic stages develop microcephaly, and that females in particular are prone to generalized tonic-clonic seizures.

Genetics of glioblastoma: a window into its imaging and histopathologic variability.

Glioblastoma is a highly malignant brain tumor that relentlessly defies therapy. Efforts over the past decade have begun to tease out the biochemical details that lead to its aggressive behavior and poor prognosis. There is hope that this new understanding will lead to improved treatment strategies for patients with glioblastoma, in the form of targeted, molecularly based therapies that are individualized to specific changes in individual tumors.

Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo.

MicroRNAs (miRNAs) are small, noncoding RNAs that play a critical role in developmental and physiological processes and are implicated in the pathogenesis of several human diseases, including cancer. They function by regulating target gene expression post-transcriptionally. In this study, we examined the role of oncogenic mir-21 in the pathogenesis of glioblastoma, the most aggressive form of primary brain tumor.

Inhibitor of DNA binding 4 (ID4) regulation of adipocyte differentiation and adipose tissue formation in mice.

Inhibitor of DNA binding 4 (ID4) is a helix-loop-helix protein that heterodimerizes with basic helix-loop-helix transcription factors inhibiting their function. ID4 expression is important for adipogenic differentiation of the 3T3-L1 cell line, and inhibition of ID4 is associated with a concomitant decrease in CCAAT/enhancer-binding protein alpha and peroxisome proliferator-activated receptor gamma mRNA and protein expression. Mice with a homozygous deletion of Id4 (Id4(-/-)) have reduced body fat and gain much less weight compared with wild-type littermates when placed on diets with high fat content.

ID2 (inhibitor of DNA binding 2) is a rhythmically expressed transcriptional repressor required for circadian clock output in mouse liver.

Id2 is a helix-loop-helix transcription factor gene expressed in a circadian manner in multiple tissues with a phase-locked relationship with canonical clock genes. Our previous studies have identified circadian phenotypes in Id2 null mice, including enhanced photo-entrainment and disruption of activity rhythms, and have demonstrated a potent inhibitory effect of ID proteins upon CLOCK-BMAL1 transactivation of clock gene and clock-controlled gene activity. We have now begun to explore the potential role that ID2 may play in specifically regulating clock output.

A role for Id2 in regulating photic entrainment of the mammalian circadian system.

Inhibitor of DNA binding genes (Id1-Id4) encode helix-loop-helix (HLH) transcriptional repressors associated with development and tumorigenesis [1, 2], but little is known concerning the function(s) of these genes in normal adult animals. Id2 was identified in DNA microarray screens for rhythmically expressed genes [3-5], and further analysis revealed a circadian pattern of expression of all four Id genes in multiple tissues including the suprachiasmatic nucleus. To explore an in vivo function, we generated and characterized deletion mutations of Id2 and of Id4.

Id2 is required for specification of dopaminergic neurons during adult olfactory neurogenesis.

Understanding the biology of adult neural stem cells has important implications for nervous system development and may contribute to our understanding of neurodegenerative disorders and their treatment. We have characterized the process of olfactory neurogenesis in adult mice lacking inhibitor of DNA binding 2(-/-) (Id2(-/-)). We found a diminished olfactory bulb containing reduced numbers of granular and periglomerular neurons with a distinct paucity of dopaminergic periglomerular neurons.

Cancer stem cells are enriched in the side population cells in a mouse model of glioma.

The recent identification of cancer stem cells (CSCs) in multiple human cancers provides a new inroad to understanding tumorigenesis at the cellular level. CSCs are defined by their characteristics of self-renewal, multipotentiality, and tumor initiation upon transplantation. By testing for these defining characteristics, we provide evidence for the existence of CSCs in a transgenic mouse model of glioma, S100beta-verbB;Trp53.

Spinal glioma: platelet-derived growth factor B-mediated oncogenesis in the spinal cord.

Human platelet-derived growth factor B (hPDGFB) has been characterized in vitro and shown to mediate numerous cellular responses including glial proliferation and differentiation. Expression of PDGFB is thought to be important in the pathogenesis of glioma and several animal models of cerebral glioma based on PDGF expression have been described. To examine whether PDGF could contribute to the pathogenesis of spinal cord glioma, we developed transgenic mice that express hPDGFB under the control of a tetracycline-responsive element (TRE/hPDGFB).

Type I collagen is overexpressed in medulloblastoma as a component of tumor microenvironment.

Medulloblastoma is the most common malignant brain tumor of children, and more specific and effective therapeutic management needs to be developed to improve upon existing survival rates and to avoid side-effects from current treatment. Gain of chromosome seven is the most frequent chromosome copy number aberration in medulloblastoma, suggesting that overexpression of genes on chromosome seven might be important for the pathogenesis of medulloblastoma. We used microarrays to identify chromosome seven genes overexpressed in medulloblastoma specimens, and validated using data from published gene expression datasets.

Characterization of microRNA expression levels and their biological correlates in human cancer cell lines.

MicroRNAs are small noncoding RNAs that function by regulating target gene expression posttranscriptionally. They play a critical role in developmental and physiologic processes and are implicated in the pathogenesis of several human diseases including cancer. We examined the expression profiles of 241 human microRNAs in normal tissues and the NCI-60 panel of human tumor-derived cell lines.

Exploratory Visual Analysis of statistical results from microarray experiments comparing high and low grade glioma.

The biological interpretation of gene expression microarray results is a daunting challenge. For complex diseases such as cancer, wherein the body of published research is extensive, the incorporation of expert knowledge provides a useful analytical framework. We have previously developed the Exploratory Visual Analysis (EVA) software for exploring data analysis results in the context of annotation information about each gene, as well as biologically relevant groups of genes.