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Jon C Aster

Publications and source records attributed to Jon C Aster.

53 records · Page 3Linked to original sources
PubMed2003

The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma.

Mediastinal large B-cell lymphoma (MLBCL) is a recently identified subtype of diffuse large B-cell lymphoma (DLBCL) that characteristically presents as localized tumors in young female patients. Although MLBCL has distinctive pathologic features, it clinically resembles the nodular sclerosis subtype of classical Hodgkin lymphoma (cHL). To elucidate the molecular features of MLBCL, we compared the gene expression profiles of newly diagnosed MLBCL and DLBCL and developed a classifier of these diseases. MLBCLs had low levels of expression of multiple components of the B-cell receptor signaling cascade, a profile resembling that of Reed-Sternberg cells of cHL. Like cHLs, MLBCLs also had high levels of expression of the interleukin-13 (IL-13) receptor and downstream effectors of IL-13 signaling (Janus kinase-2 [JAK2] and signal transducer and activator of transcription-1 [STAT1]), tumor necrosis factor (TNF) family members, and TNF receptor-associated factor-1 (TRAF1). Increased expression of STAT1 and TRAF1 in MLBCL was confirmed by immunohistochemistry. Given the TRAF1 expression and known link to nuclear factor-kappa B (NF- kappa B), MLBCLs were also evaluated for nuclear translocation of c-REL protein. In almost all cases, c-REL was localized to the nucleus, consistent with activation of the NF-kappa B pathway. These studies identify a molecular link between MLBCL and cHL and a shared survival pathway.

Active Transport, Cell Nucleus↗
PubMed2003

Cloning of the t(1;5)(q23;q33) in a myeloproliferative disorder associated with eosinophilia: involvement of PDGFRB and response to imatinib.

Eosinophilia is common in myeloproliferative disorders (MPDs) with abnormalities of chromosome band 5q31-33, including those that present with t(1;5)(q23;q33). With the development of rational drug therapy, characterization of the molecular targets for these translocations could guide treatment and affect patient survival. We cloned the t(1;5)(q23;q33) and showed that it fuses platelet-derived growth factor receptor beta (PDGFRB) to the coiled-coil domains of a novel partner protein, myomegalin. Using two-color interphase fluorescence in situ hybridization (FISH), we also demonstrated that the eosinophils are clonal in these disorders. Imatinib mesylate has recently been shown to be efficacious in MPDs with PDGFR activation. Therefore, following our molecular studies, we were able to redirect this patient's treatment. Although she had refractory and progressive disease, once imatinib was started, complete clinical and hematologic remission, as well as major cytogenetic response, was achieved. Given the therapeutic implications, our findings stress the need to aggressively investigate the molecular basis of these diseases, with emphasis on the PDGFR family.

Benzamides↗
PubMed2003

Nuclear magnetic resonance structure of a prototype Lin12-Notch repeat module from human Notch1.

Notch1 is a member of a conserved family of large modular heterodimeric type 1 transmembrane receptors that control differentiation in multicellular animals. Receptor maturation is accompanied by a furin-dependent cleavage that converts the Notch1 precursor polypeptide into a heterodimer consisting of an extracellular ligand-binding subunit (NEC) and a transmembrane signaling subunit (NTM). Binding of a physiologic ligand to NEC induces signaling by triggering additional proteolytic cleavages in NTM, which allow its intracellular region to translocate to the nucleus where it participates in a transcriptional activation complex. In the absence of ligand, the three conserved LNR modules of the NEC subunit participate in maintaining the receptor in its resting conformation. Here, we report the solution structure of the first LNR module (LNR_A) of human Notch1, and identify residues of LNR_A perturbed by the presence of the adjacent module LNR_B. LNR_A is held together by a unique arrangement of three disulfide bonds and a single bound Ca(2+) ion, and adopts a novel fold that falls in the general class of irregular disulfide-bonded structures. Residues perturbed by the presence of the adjacent LNR_B module are predominantly hydrophobic, and lie on one face of the module. These studies represent an initial step toward understanding the structural interrelationships among the three contiguous LNR modules required for proper regulation of Notch signaling.

Amino Acid Sequence↗
PubMed2003

The BAL-binding protein BBAP and related Deltex family members exhibit ubiquitin-protein isopeptide ligase activity.

Members of the DTX (Deltex) family act as Notch signaling modifiers and may also regulate transcription through interactions with specific transcription factors. DTX proteins have a basic N terminus; a central proline-rich region; and a C-terminal RING finger domain, a motif often found in ubiquitin-protein isopeptide ligases (E3). Recently, we identified and characterized a unique diffuse large B-cell lymphoma risk-related gene named BAL (B aggressive lymphoma). Using a yeast two-hybrid screen for BAL-binding partners, we have now identified a novel protein termed BBAP (B-lymphoma- and BAL-associated protein). Although BBAP has a unique N terminus, the C-terminal region is highly homologous to that of DTX family members. Herein, we report that BBAP and the human family of DTX proteins (DTX1, DTX2, and DTX3) function as E3 ligases based on their capacity for self-ubiquitination. DTX family members homodimerize and heterodimerize in vivo, suggesting that physical interactions between various DTX family members modify E3 activity and/or substrate availability. Consistent with this idea, BBAP and DTX1 associate via their unique N termini, resulting in enhanced self-ubiquitination.

Amino Acid Sequence↗
PubMed2003

Structural requirements for assembly of the CSL.intracellular Notch1.Mastermind-like 1 transcriptional activation complex.

Ligand binding by Notch receptors triggers a series of proteolytic cleavages that liberate the intracellular portion of Notch (ICN) from the cell membrane, permitting it to translocate to the nucleus. Nuclear ICN binds to a highly conserved DNA-binding transcription factor called CSL (also known as RBP-Jkappa, CBF1, Suppressor of Hairless, and Lag-1) and recruits Mastermind-like transcriptional co-activators to form a transcriptional activation complex. Using bioinformatics tools, we identified a Rel homology region (RHR) within CSL that was used as a guide to determine the minimal protein requirements for ternary complex formation. The RHR of CSL contains both the N- and C-terminal beta-sheet domains (RHR-n and RHR-c) of typical Rel transcription factors, as judged by circular dichroism spectra. Binding of monomeric CSL to DNA requires the entire RHR of CSL and an additional 125-residue N-terminal sequence, whereas binding to ICN requires only the RHR-n domain. Although the RAM (RBP-Jkappa (recombination-signal-sequence-binding protein for Jkappa genes)-associated molecule) domain of ICN is flexible and relatively unstructured as an isolated polypeptide in solution, it associates stably with CSL on DNA. Recruitment of Mastermind-like 1 (MAML1) to CSL.ICN complexes on DNA requires inclusion of the ankyrin repeat domain of ICN, and N- and C-terminal sequences of CSL extending beyond the DNA-binding region. The requirement for cooperative assembly of the MAML1.ICN.CSL.DNA complex suggests that a primary function of ICN is to render CSL competent for MAML loading. On the basis of our results, we present a working structural model for the organization of the MAML1.ICN.CSL.DNA complex.

Ankyrins↗
PubMed2003

Myc-induced T cell leukemia in transgenic zebrafish.

The zebrafish is an attractive model organism for studying cancer development because of its genetic accessibility. Here we describe the induction of clonally derived T cell acute lymphoblastic leukemia in transgenic zebrafish expressing mouse c-myc under control of the zebrafish Rag2 promoter. Visualization of leukemic cells expressing a chimeric transgene encoding Myc fused to green fluorescent protein (GFP) revealed that leukemias arose in the thymus, spread locally into gill arches and retro-orbital soft tissue, and then disseminated into skeletal muscle and abdominal organs. Leukemic cells homed back to the thymus in irradiated fish transplanted with GFP-labeled leukemic lymphoblasts. This transgenic model provides a platform for drug screens and for genetic screens aimed at identifying mutations that suppress or enhance c-myc- induced carcinogenesis.

Animals↗
PubMed2003

Growth suppression of pre-T acute lymphoblastic leukemia cells by inhibition of notch signaling.

Constitutive NOTCH signaling in lymphoid progenitors promotes the development of immature T-cell lymphoblastic neoplasms (T-ALLs). Although it is clear that Notch signaling can initiate leukemogenesis, it has not previously been established whether continued NOTCH signaling is required to maintain T-ALL growth. We demonstrate here that the blockade of Notch signaling at two independent steps suppresses the growth and survival of NOTCH1-transformed T-ALL cells. First, inhibitors of presenilin specifically induce growth suppression and apoptosis of a murine T-ALL cell line that requires presenilin-dependent proteolysis of the Notch receptor in order for its intracellular domain to translocate to the nucleus. Second, a 62-amino-acid peptide derived from a NOTCH coactivator, Mastermind-like-1 (MAML1), forms a transcriptionally inert nuclear complex with NOTCH1 and CSL and specifically inhibits the growth of both murine and human NOTCH1-transformed T-ALLs. These studies show that continued growth and survival of NOTCH1-transformed lymphoid cell lines require nuclear access and transcriptional coactivator recruitment by NOTCH1 and identify at least two steps in the Notch signaling pathway as potential targets for chemotherapeutic intervention.

Alleles↗
PubMed2002

Molecular biology of anaplastic lymphoma kinase-positive anaplastic large-cell lymphoma.

Anaplastic large-cell lymphoma (ALCL) provides an excellent example of how molecular insights into tumor pathogenesis are influencing and improving tumor classification. ALCL was described initially as a subtype of T-cell/null-cell lymphoma characterized by unusual tumor cell morphology and the expression of CD30. However, it was soon recognized that a subset of ALCLs contained chromosomal translocations involving anaplastic lymphoma kinase (ALK), a novel receptor tyrosine kinase gene. These rearrangements create chimeric genes encoding self-associating, constitutively active ALK fusion proteins that activate a number of downstream effectors, including phospholipase C-gamma, phosphoinositol 3'-kinase, RAS, and signal transducer and activator of transcription proteins, all of which seem potentially important in cellular transformation. Not all tumors classified as ALCLs have ALK rearrangements and, conversely, ALK rearrangements occur in lymphomas of widely varying morphology. Hence, only molecular markers can reliably identify ALK+ ALCL. The importance of doing so is reflected by clinical studies suggesting that ALK+ ALCLs have a significantly better prognosis than other aggressive peripheral T-cell or B-cell lymphomas, including ALK- ALCLs. The unique molecular pathogenesis of ALK+ ALCL is likely to lead to novel therapeutic approaches directed at specific inhibition of ALK or downstream effectors.

Anaplastic Lymphoma Kinase↗
PubMed2002

Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells.

Truncated Notch receptors have transforming activity in vitro and in vivo. However, the role of wild-type Notch signaling in neoplastic transformation remains unclear. Ras signaling is deregulated in a large fraction of human malignancies and is a major target for the development of novel cancer treatments. We show that oncogenic Ras activates Notch signaling and that wild-type Notch-1 is necessary to maintain the neoplastic phenotype in Ras-transformed human cells in vitro and in vivo. Oncogenic Ras increases levels and activity of the intracellular form of wild-type Notch-1, and upregulates Notch ligand Delta-1 and also presenilin-1, a protein involved in Notch processing, through a p38-mediated pathway. These observations place Notch signaling among key downstream effectors of oncogenic Ras and suggest that it might be a novel therapeutic target.

Animals↗
PubMed2002

An invitation to T and more: notch signaling in lymphopoiesis.

Cell fate decisions in metazoans are regulated by Notch signals. During lymphoid development, Notch influences a series of cell fate decisions involving multipotent progenitors. This review focuses on current views and lingering uncertainties about Notch function in lymphoid cells.

Animals↗
PubMed2002

Deltex1 redirects lymphoid progenitors to the B cell lineage by antagonizing Notch1.

Notch1 signaling drives T cell development at the expense of B cell development from a common precursor, an effect that is dependent on a C-terminal Notch1 transcriptional activation domain. The function of Deltex1, initially identified as a positive modulator of Notch function in a genetic screen in Drosophila, is poorly understood. We now demonstrate that, in contrast to Notch1, enforced expression of Deltex1 in hematopoietic progenitors results in B cell development at the expense of T cell development in fetal thymic organ culture and in vivo. Consistent with these effects, Deltex1 antagonizes Notch1 signaling in transcriptional reporter assays by inhibiting coactivator recruitment. These data suggest that a balance of inductive Notch1 signals and inhibitory signals mediated through Deltex1 and other modulators regulate T-B lineage commitment.

3T3 Cells↗
PubMed2002

Notch signaling as a therapeutic target.

Signals transduced by Notch receptors influence differentiation and proliferation in a wide variety of cell types. Activation of a Notch signal by one of several ligands triggers a series of proteolytic cleavages that release the intracellular region of Notch from the membrane, allowing it ultimately to translocate to the nucleus and activate the transcription of downstream target genes. Recent studies have elucidated the roles of several key proteins that participate in and modulate these central events in Notch signal transduction. These advances offer a variety of potential avenues to manipulate Notch signaling for therapeutic purposes in the treatment of cancer and in stem cell maintenance.

Drug Delivery Systems↗
PubMed2002

Notch signaling in hematopoiesis and early lymphocyte development.

Notch signals regulate multiple cell fate decisions during metazoan development. During hematopoiesis, Notch affects both hematopoietic stem cells and committed progenitors. In hematopoietic stem cells, Notch signaling has the propensity to expand the stem cells, promote their self-renewal, and influence their survival. In committed progenitors, Notch signaling plays a key role in determining lymphoid cell fates. This review focuses on recent developments to understand the role of Notch signaling in early events in hematopoiesis.

Animals↗
PubMed2002

Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning.

Diffuse large B-cell lymphoma (DLBCL), the most common lymphoid malignancy in adults, is curable in less than 50% of patients. Prognostic models based on pre-treatment characteristics, such as the International Prognostic Index (IPI), are currently used to predict outcome in DLBCL. However, clinical outcome models identify neither the molecular basis of clinical heterogeneity, nor specific therapeutic targets. We analyzed the expression of 6,817 genes in diagnostic tumor specimens from DLBCL patients who received cyclophosphamide, adriamycin, vincristine and prednisone (CHOP)-based chemotherapy, and applied a supervised learning prediction method to identify cured versus fatal or refractory disease. The algorithm classified two categories of patients with very different five-year overall survival rates (70% versus 12%). The model also effectively delineated patients within specific IPI risk categories who were likely to be cured or to die of their disease. Genes implicated in DLBCL outcome included some that regulate responses to B-cell-receptor signaling, critical serine/threonine phosphorylation pathways and apoptosis. Our data indicate that supervised learning classification techniques can predict outcome in DLBCL and identify rational targets for intervention.

Antineoplastic Combined Chemotherapy Protocols↗
PubMedDate not supplied

Notch signaling in cancer.

Notch signaling plays a key role in the normal development of many tissues and cell types, through diverse effects on differentiation, survival, and/or proliferation that are highly dependent on signal strength and cellular context. Because perturbations in the regulation of differentiation, survival, and/or proliferation underlie malignant transformation, pathophysiologic Notch signals potentially contribute to cancer development in several different ways. Notch signaling was first linked to tumorigenesis through identification of a recurrent t(7;9)(q34;q34.3) chromosomal translocation involving the human Notch1 gene that is found in a small subset of human pre-T-cell acute lymphoblastic leukemias (T-ALL).(1) Since this discovery, aberrant Notch signaling has been suggested to be involved in a wide variety of human neoplasms. In this review, we will focus on recent studies linking aberrant Notch signaling with cancer. First, we discuss various mechanisms through which Notch signaling may influence cellular transformation. Then, we critically review literature pertaining to the role of Notch signaling in several cancers, and discuss possible therapeutic targets in the Notch pathway.

Animals↗