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Biomedical subjects

Andrew P Weng

Publications and source records attributed to Andrew P Weng.

17 recordsLinked to original sources
PubMed2007

Expression of TRAF1 and nuclear c-Rel distinguishes primary mediastinal large cell lymphoma from other types of diffuse large B-cell lymphoma.

Primary mediastinal large B-cell lymphoma (PMLBCL) is a recently identified subtype of diffuse large B-cell lymphoma (DLBCL) that is difficult to distinguish from other types of DLBCL on the basis of histologic features alone. We recently identified a molecular signature of PMLBCL that is distinct from other forms of DLBCL but shares features with classical Hodgkin lymphoma. This signature includes activation of the nuclear factor kappaB (NFkappaB) signaling pathway, which in part, acts through nuclear translocation of c-Rel containing NFkappaB transcriptional complexes, and subsequent expression of NFkappaB target genes such as tumor necrosis factor receptor-associated factor-1 (TRAF1). Using standard immunohistochemical techniques, we examined 251 large B-cell lymphomas (78 cases of PMLBCL and 173 cases of other types of DLBCL) to determine whether the expression patterns of c-Rel and TRAF1 could reliably distinguish between PMLBCL and other types of DLBCL. Robust nuclear c-Rel was present in 31 of 48 (65%) cases of PMLBCL and 28 of 160 (18%) cases of DLBCL. In addition, cytoplasmic TRAF1 expression was seen in 48 of 78 (62%) cases of PMLBCL, but only 20 of 173 (12%) cases of DLBCL. Finally, the combined expression of nuclear c-Rel and TRAF1 was seen in 24 of 45 cases (53%) of PMLBCL, but in only 3 of 156 cases (2%) of other types of DLBCL. Thus, the combined nuclear localization of c-Rel and the cellular expression of TRAF1 is a highly specific (specificity=98%) means to distinguish PMLBCL from DLBCL that is readily applicable to routine surgical pathology practice.

Biomarkers, Tumor↗
PubMed2006

NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth.

The NOTCH1 signaling pathway directly links extracellular signals with transcriptional responses in the cell nucleus and plays a critical role during T cell development and in the pathogenesis over 50% of human T cell lymphoblastic leukemia (T-ALL) cases. However, little is known about the transcriptional programs activated by NOTCH1. Using an integrative systems biology approach we show that NOTCH1 controls a feed-forward-loop transcriptional network that promotes cell growth. Inhibition of NOTCH1 signaling in T-ALL cells led to a reduction in cell size and elicited a gene expression signature dominated by down-regulated biosynthetic pathway genes. By integrating gene expression array and ChIP-on-chip data, we show that NOTCH1 directly activates multiple biosynthetic routes and induces c-MYC gene expression. Reverse engineering of regulatory networks from expression profiles showed that NOTCH1 and c-MYC govern two directly interconnected transcriptional programs containing common target genes that together regulate the growth of primary T-ALL cells. These results identify c-MYC as an essential mediator of NOTCH1 signaling and integrate NOTCH1 activation with oncogenic signaling pathways upstream of c-MYC.

Cell Line↗
PubMed2006

c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma.

Human acute T-cell lymphoblastic leukemias and lymphomas (T-ALL) are commonly associated with gain-of-function mutations in Notch1 that contribute to T-ALL induction and maintenance. Starting from an expression-profiling screen, we identified c-myc as a direct target of Notch1 in Notch-dependent T-ALL cell lines, in which Notch accounts for the majority of c-myc expression. In functional assays, inhibitors of c-myc interfere with the progrowth effects of activated Notch1, and enforced expression of c-myc rescues multiple Notch1-dependent T-ALL cell lines from Notch withdrawal. The existence of a Notch1-c-myc signaling axis was bolstered further by experiments using c-myc-dependent murine T-ALL cells, which are rescued from withdrawal of c-myc by retroviral transduction of activated Notch1. This Notch1-mediated rescue is associated with the up-regulation of endogenous murine c-myc and its downstream transcriptional targets, and the acquisition of sensitivity to Notch pathway inhibitors. Additionally, we show that primary murine thymocytes at the DN3 stage of development depend on ligand-induced Notch signaling to maintain c-myc expression. Together, these data implicate c-myc as a developmentally regulated direct downstream target of Notch1 that contributes to the growth of T-ALL cells.

Animals↗
PubMed2005

Notch signaling in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is a form of pediatric leukemia that is thought to be caused by approximately 12 distinct chromosomal translocations that lead to aberrant expression of as many different cellular genes. Development of novel, rational therapies against such a diverse set of mechanistic targets has thus been a formidable challenge. Recent studies, however, have identified a large fraction of T-ALL cases carrying mutations in one of these genes, Notch1, suggesting for the first time that many cases may share a common pathogenic etiology, and perhaps may allow the development of targeted therapies that benefit the majority of patients with this disease.

Animals↗
PubMed2004

Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia.

Very rare cases of human T cell acute lymphoblastic leukemia (T-ALL) harbor chromosomal translocations that involve NOTCH1, a gene encoding a transmembrane receptor that regulates normal T cell development. Here, we report that more than 50% of human T-ALLs, including tumors from all major molecular oncogenic subtypes, have activating mutations that involve the extracellular heterodimerization domain and/or the C-terminal PEST domain of NOTCH1. These findings greatly expand the role of activated NOTCH1 in the molecular pathogenesis of human T-ALL and provide a strong rationale for targeted therapies that interfere with NOTCH signaling.

Adolescent↗
PubMed2004

Mastermind critically regulates Notch-mediated lymphoid cell fate decisions.

During lymphoid development, Notch1 plays a critical role in the T-cell/B-cell lineage decision, while Notch2 is essential for marginal zone B-cell (MZB) development. Notch pathway activation induces translocation of intracellular Notch (ICN) to the nucleus, where it interacts with the transcription factor CSL (CBF1/RBP-Jk, Suppressor of Hairless, Lag-1). In vitro, ICN binds Mastermind-like proteins, which act as potent Notch coactivators. Three MAML family members (MAML1-3) have been identified in mammals, but their importance in vivo is unknown. To investigate the function of MAMLs in hematopoietic development, we introduced a dominant negative (DN) mutant of MAML1, capable of inhibiting Notch1-4, in murine hematopoietic stem cells. DNMAML1 resulted in early inhibition of T-cell development and the appearance of intrathymic B cells, phenotypes consistent with Notch1 inhibition. The T-cell differentiation block was as profound as that produced by enforced expression of the Notch modulator Deltex1. In DNMAML1-transduced spleen cells, a dramatic decrease in MZB cells was present, consistent with Notch2 inhibition. In contrast, Deltex1 did not decrease MZB cell numbers. These results suggest a critical role for MAMLs during Notch-mediated cell fate decisions in vivo and indicate that DNMAML1, but not Deltex1, can be used to interfere with the function of multiple Notch family members.

Animals↗
PubMed2004

Notch oncoproteins depend on gamma-secretase/presenilin activity for processing and function.

During normal development Notch receptor signaling is important in regulating numerous cell fate decisions. Mutations that truncate the extracellular domain of Notch receptors can cause aberrant signaling and promote unregulated cell growth. We have examined two types of truncated Notch oncoproteins that arise from proviral insertion into the Notch4 gene (Notch4/int-3) or a chromosomal translocation involving the Notch1 gene (TAN-1). Both Notch4/int-3 and TAN-1 oncoproteins lack most or all of their ectodomain. Normal Notch signaling requires gamma-secretase/presenilin-mediated proteolytic processing, but whether Notch oncoproteins are also dependent on gamma-secretase/presenilin activity is not known. We demonstrate that Notch4/int-3-induced activation of the downstream transcription factor, CSL, is abrogated in cells deficient in presenilins or treated with a pharmacological inhibitor of gamma-secretase/presenilins. Furthermore, we find that both Notch4/int-3 and TAN-1 accumulate at the cell surface, where presenilin-dependent cleavage occurs, when gamma-secretase/presenilin activity is inhibited. gamma-Secretase/presenilin inhibition effectively blocks cellular responses to Notch4/int-3, but not TAN-1, apparently because some TAN-1 polypeptides lack transmembrane domains and do not require gamma-secretase/presenilin activity for nuclear access. These studies highlight potential uses and limitations of gamma-secretase/presenilin inhibitors in targeted therapy of Notch-related neoplasms.

Adenoviridae↗
PubMed2004

Multiple niches for Notch in cancer: context is everything.

Notch receptor signaling has very distinctive roles in cancers originating from different types of cells that reflect its complex functions in normal tissue development and homeostasis. For example, recent studies have shown that Notch signals are oncogenic in pre-T cells but suppress tumor development in keratinocytes. Notch signaling contributes to pre-malignant metaplastic changes that precede pancreatic carcinoma, and it is also likely to be involved in other forms of metaplasia. In addition, several viral oncoproteins and chromosomal translocations target one or more components of a Notch transcriptional activation complex.

Humans↗
PubMed2004

Notch subunit heterodimerization and prevention of ligand-independent proteolytic activation depend, respectively, on a novel domain and the LNR repeats.

Notch proteins are transmembrane receptors that participate in a highly conserved signaling pathway that regulates morphogenesis in metazoans. Newly synthesized Notch receptors are proteolytically cleaved during transit to the cell surface, creating heterodimeric mature receptors comprising noncovalently associated extracellular (N(EC)) and transmembrane (N) subunits. Ligand binding activates Notch by inducing two successive proteolytic cleavages, catalyzed by metalloproteases and gamma-secretase, respectively, that permit the intracellular portion of N to translocate to the nucleus and activate transcription of target genes. Prior work has shown that the presence of N(EC) prevents ligand-independent activation of N, but the mechanisms involved are poorly understood. Here, we define the roles of two regions at the C-terminal end of N(EC) that participate in maintaining the integrity of resting Notch receptors through distinct mechanisms. The first region, a hydrophobic, previously uncharacterized portion of N(EC), is sufficient to form stable complexes with the extracellular portion of N. The second region, consisting of the three Lin12/Notch repeats, is not needed for heterodimerization but acts to protect N from ligand-independent cleavage by metalloproteases. Together, these two contiguous regions of N(EC) impose crucial restraints that prevent premature Notch receptor activation.

Amino Acid Motifs↗
PubMed2004

Hodgkin disease associated with T-cell non-Hodgkin lymphomas: case reports and review of the literature.

Non-Hodgkin lymphoma (NHL) is more likely to develop in patients with Hodgkin disease (HD) than in the general population. Although reports of synchronous or metachronous HD and NHL are not uncommon in the literature, the biologic relationship of these 2 malignant neoplasms often is unclear. A larger-than-expected fraction of NHLs occurring in patients with HD are of the T-cell phenotype. We report 1 synchronous and 3 metachronous cases of HD and T-cell NHL. In 2 cases, the 2 tumors are unlikely to be related clonally. In the other 2 cases, however, T-cell receptor rearrangement studies demonstrated the presence of the same rearranged clone in both tumor specimens, suggesting that they share a common precursor or that one arose by transformation of the other. These observations imply that, similar to the observations in B-cell NHLs occurring with HD, a subset of synchronous and metachronous T-cell NHLs and HD may be related clonally.

Adult↗
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

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↗
PubMed2003

Infectious diseases detected at autopsy at an urban public hospital, 1996-2001.

Previous studies have demonstrated significant discrepancy rates between clinical and autopsy diagnoses. However, infectious diseases have not received emphasis in these studies. We conducted a study to determine whether the clinical and autopsy diagnoses of infectious diseases are concordant or discrepant and to determine discrepancy rates. Retrospective reviews of the records of 276 patients (adults, 182; fetuses and neonates, 94) who underwent autopsy during the years 1996 through 2001 were performed. Comparison of clinical and autopsy diagnoses was performed using the Goldman classification scheme. Of 182 adult patients, 137 (75.3%) had an infectious disease at autopsy. In 59 (43.1%) of 137 patients, the infectious disease diagnoses were unknown clinically. Of 94 fetuses and neonates, 45 (48%) had an infectious disease at autopsy. In 26 (58%) of 45 patients, the infectious disease diagnoses were unknown before death. There are substantial discrepancies between clinical and autopsy diagnoses of infectious diseases. In adults, acute bronchopneumonia is the infectious disease most often missed clinically; in fetuses and neonates, it is acute chorioamnionitis.

Adult↗
PubMed2003

CXCR4/CD184 immunoreactivity in T-cell non-Hodgkin lymphomas with an overall Th1- Th2+ immunophenotype.

We performed an immunohistochemical analysis of CXCR4/CD184 expression in frozen and paraffin-embedded sections of human peripheral T-cell lymphomas that exhibit a composite Th1 T-cell-like or Th2 T-cell-like immunophenotype, based on expression of Th1-associated markers (CXCR3, OX40/CD134, and CD69) and Th2-associated markers (CD30 and CCR4). In 66 cases examined, CXCR4/CD184 expression correlated significantly with immunoreactivity for other markers of Th2 differentiation (P < .0001). Anaplastic large cell lymphoma, which typically expresses markers of Th2 differentiation, was immunoreactive for CXCR4/CD184 in 22 (88%) of 25 cases. Tumors previously identified as exhibiting a composite Th1-like immunophenotype, which include angioimmunoblastic lymphoma, lymphoepithelioid lymphoma, and other peripheral T-cell lymphomas now termed unspecified, were positive for CXCR4/CD184 in 7 (17%) of 41 cases. These results are consistent with previous findings that a subset of peripheral T-cell lymphomas can be divided into Th1-like and Th2-like categories based on immunoreactivity with a limited set of markers. Our findings also suggest that CXCR4/CD184, which is expressed by a number of malignant neoplasms and may have a role in tumor metastasis, may have a similar function in CXCR4+ T-cell non-Hodgkin lymphomas.

Antigens, CD↗
PubMed2002

Expression of geminin as a marker of cell proliferation in normal tissues and malignancies.

Geminin interacts with a DNA replication initiation factor, Cdt1p, to suppress initiation of DNA replication in a Xenopus egg extract based cell-free system, leading to the expectation that the protein acts as an inhibitor of cell proliferation. Immunohistochemistry and immunoblotting for geminin, however, reveals that the protein is expressed specifically in proliferating lymphocytes and epithelial cells. This pattern is in contrast to the expression of a bona fide cell cycle inhibitor like p21/WAF1 that is specifically expressed in quiescent cells. Geminin is widely expressed in several malignancies and the number of geminin-expressing cells is directly proportional to the cell proliferation index as measured by Ki-67 expression. Therefore, instead of being a suppressor of cell proliferation, geminin expression is positively correlated with cell proliferation. Consistent with this observation, transient overexpression of wild-type geminin in cancer cells in culture did not produce a cell cycle block. A point mutation in the destruction box of geminin, however, results in a protein that is stabilized in G(1) and capable of arresting cells at the G(1)-S transition.

Biomarkers↗
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↗