Biomedical subjects

Suzanne Cory

Publications and source records attributed to Suzanne Cory.

10 recordsLinked to original sources

PubMed2006

MYC levels govern hematopoietic tumor type and latency in transgenic mice.

Deregulated MYC expression has been implicated in the etiology of many human cancers, including hematopoietic malignancies. To explore the impact of widespread constitutive MYC expression in the hematopoietic compartment, we have used a vector containing regulatory elements of the Vav gene to generate transgenic mice. VavP-MYC mice are highly tumor-prone and the level of MYC was found to influence both the kinetics and nature of the malignancies that developed. Whereas aggressive T-cell lymphomas rapidly overwhelmed the highest-expressing line, late-onset monocytic tumors greatly predominated in 2 low-expressing lines. These monocytic tumors most likely arise from abnormal macrophage colony-stimulating factor (M-CSF)-dependent progenitor cells having enhanced self-generative capacity. There appears to be a sharp threshold for MYC-induced T-cell lymphomagenesis because merely doubling the MYC level in a low-expressing line by breeding homozygous transgenic animals switched the phenotype from primarily monocytic tumors to exclusively T-cell tumors. Even the low level of MYC, however, clearly affected T-cell cycling, size, and sensitivity to apoptosis, and coexpression of a BCL2 transgene promoted efficient T-cell lymphomagenesis. The implication is that MYC level affects the spontaneous acquisition of synergistic oncogenic mutations.

Animals↗

PubMed2006

The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized.

Since apoptosis is impaired in malignant cells overexpressing prosurvival Bcl-2 proteins, drugs mimicking their natural antagonists, BH3-only proteins, might overcome chemoresistance. Of seven putative BH3 mimetics tested, only ABT-737 triggered Bax/Bak-mediated apoptosis. Despite its high affinity for Bcl-2, Bcl-x(L), and Bcl-w, many cell types proved refractory to ABT-737. We show that this resistance reflects ABT-737's inability to target another prosurvival relative, Mcl-1. Downregulation of Mcl-1 by several strategies conferred sensitivity to ABT-737. Furthermore, enforced Mcl-1 expression in a mouse lymphoma model conferred resistance. In contrast, cells overexpressing Bcl-2 remained highly sensitive to ABT-737. Hence, ABT-737 should prove efficacious in tumors with low Mcl-1 levels, or when combined with agents that inactivate Mcl-1, even to treat those tumors that overexpress Bcl-2.

Animals↗

PubMed2005

T-cell lymphomas mask slower developing B-lymphoid and myeloid tumours in transgenic mice with broad haemopoietic expression of MYC.

Deregulation of MYC expression occurs in many haematological malignancies. Previous studies modelling MYC-induced lymphomagenesis in the mouse used transgenic vectors that directed MYC overexpression in a lineage-specific manner. Here, we describe a transgenic mouse strain in which constitutive MYC expression is driven broadly in haemopoiesis by a vector containing regulatory elements of the Vav gene. Healthy young VavP-MYC17 mice had multiple haemopoietic abnormalities, most notably increased size and numbers of B-lymphoid cells, monocytes and megakaryocytes. The mice rapidly developed tumours and, surprisingly, these were exclusively T-cell lymphomas, mostly of mature CD4(+) CD8(-) T cells, a tumour type that is seldom seen in mouse models. To examine tumour development in the absence of the susceptible T cells, we bred VavP-MYC17 mice lacking the Rag1 recombinase. They survived longer and succumbed to tumours of several different haemopoietic cell types: pre-T cells, pro-B cells, macrophages and unusual progenitor cells. Thus, although T-lineage cells have the shortest latent period to transformation, the VavP-MYC17 transgene drives malignant transformation of multiple cell types and VavP-MYC17 mice provide a new model for tumours of multiple haemopoietic lineages.

Animals↗

PubMed2005

Killing cancer cells by flipping the Bcl-2/Bax switch.

Impairment of apoptosis, the physiologic cell death process, is central to cancer development and renders tumors refractory to cytotoxic therapy. Bcl-2, the oncoprotein activated in follicular lymphoma, inhibits the conserved cell death pathway triggered by diverse cytotoxic agents, as do several close relatives. A small-molecule antagonist of these proteins has now been designed by Oltersdorf et al. Strikingly, ABT-737 sensitizes many tumors to cytotoxic agents and is effective as a single agent against certain lymphomas and solid tumors, provoking stable regression in some tumor xenografts. Hence, this work validates Bcl-2-like proteins as important new targets in cancer therapy.

Apoptosis↗

PubMed2004

Bim is a suppressor of Myc-induced mouse B cell leukemia.

Impaired apoptosis is now recognized to be central to tumor development. Bcl2, activated by chromosomal translocation in human follicular lymphoma, promotes oncogenesis by inhibiting apoptosis. Bim, a distant proapoptotic relative, is emerging as a major physiologic antagonist of Bcl2. Here, we show that loss of Bim is oncogenic. Bim protein levels were elevated in the apoptosis-prone B lymphoid cells of Emicro-Myc-transgenic mice, and Bim-mutant Emicro-Myc mice had increased numbers of IgM-bearing B cells. Emicro-Myc-expressing B lymphoid cells deficient in Bim were refractory to apoptosis induced in vitro by cytokine deprivation or antigen receptor cross-linking. Thus, Bim is induced by Myc in B cells and mediates apoptosis. Remarkably, inactivation of even a single allele of Bim accelerated Myc-induced development of tumors, particularly acute B cell leukemia. None of the primary tumors from Bim(+/-) Emicro-Myc mice displayed loss of the second allele of Bim. These findings indicate that Bim is a tumor suppressor, at least in B lymphocytes, and is haploinsufficient. Whereas the p19Arf/p53 pathway is frequently mutated in tumors arising in Bim(+/+) Emicro-Myc mice, it was unaffected in most Bim-deficient tumors, indicating that Bim reduction is an effective alternative to loss of p53 function.

Alleles↗

PubMed2003

The Bcl-2 family: roles in cell survival and oncogenesis.

Apoptosis, the cell-suicide programme executed by caspases, is critical for maintaining tissue homeostasis, and impaired apoptosis is now recognized to be a key step in tumorigenesis. Whether a cell should live or die is largely determined by the Bcl-2 family of anti- and proapoptotic regulators. These proteins respond to cues from various forms of intracellular stress, such as DNA damage or cytokine deprivation, and interact with opposing family members to determine whether or not the caspase proteolytic cascade should be unleashed. This review summarizes current views of how these proteins sense stress, interact with their relatives, perturb organelles such as the mitochondrion and endoplasmic reticulum and govern pathways to caspase activation. It briefly explores how family members influence cell-cycle entry and outlines the evidence for their involvement in tumour development, both as oncoproteins and tumour suppressors. Finally, it discusses the promise of novel anticancer therapeutics that target these vital regulators.

Animals↗

PubMed2003

VavP-Bcl2 transgenic mice develop follicular lymphoma preceded by germinal center hyperplasia.

In human follicular lymphoma the t(14; 18) chromosome translocation activates the antiapoptotic oncogene Bcl2 by linking it to the immunoglobulin heavy chain (IGH) locus. Transgenic mice expressing Bcl2 controlled by an Igh enhancer (E mu) do not develop follicular lymphoma, although they do have an increased incidence of other B-lymphoid neoplasms. We have now analyzed tumorigenesis in mice bearing a Bcl2 transgene controlled by Vav gene regulatory sequences (VavP), which confer expression in multiple hematopoietic lineages. Unlike E mu-Bcl2 mice, many VavP-Bcl2 mice older than 10 months developed follicular lymphoma. Young VavP-Bcl2 mice had an overabundance of enlarged germinal centers and greatly elevated numbers of cycling B cells that had undergone IgH class switching and V-gene hypermutation. The peripheral T-cell compartment was larger in the VavP-Bcl2 mice than in E mu-Bcl2 strains and, notably, CD4 T cells were 5-fold increased over normal. The germinal center hyperplasia required CD4 T cells, because it could be abolished by anti-CD4 antibody in vivo. VavP-Bcl2 mice also had a propensity to develop kidney disease of the autoimmune type. We suggest that the increased survival capacity of B and T cells fosters prolonged germinal center reactions, and that autoreactivity and hypermutation conspire to generate follicular lymphoma.

Animals↗

PubMed2002

BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes.

During lymphocyte development, the assembly of genes coding for antigen receptors occurs by the combinatorial linking of gene segments. The stochastic nature of this process gives rise to lymphocytes that can recognize self-antigens, thereby having the potential to induce autoimmune disease. Such autoreactive lymphocytes can be silenced by developmental arrest or unresponsiveness (anergy), or can be deleted from the repertoire by cell death. In the thymus, developing T lymphocytes (thymocytes) bearing a T-cell receptor (TCR)-CD3 complex that engages self-antigens are induced to undergo programmed cell death (apoptosis), but the mechanisms ensuring this 'negative selection' are unclear. We now report that thymocytes lacking the pro-apoptotic Bcl-2 family member Bim (also known as Bcl2l11) are refractory to apoptosis induced by TCR-CD3 stimulation. Moreover, in transgenic mice expressing autoreactive TCRs that provoke widespread deletion, Bim deficiency severely impaired thymocyte killing. TCR ligation upregulated Bim expression and promoted interaction of Bim with Bcl-XL, inhibiting its survival function. These findings identify Bim as an essential initiator of apoptosis in thymocyte-negative selection.

Amino Acid Sequence↗

PubMed2002

Apoptosomes: engines for caspase activation.

Activation of the caspases that initiate apoptosis typically requires cognate scaffold proteins, including CED-4 in Caenorhabditis elegans, Apaf-1 in mammals and Dark in Drosophila. Each scaffold protein oligomerizes procaspases into a complex called the apoptosome, but the regulation and biological roles of the scaffolds differ. Whereas CED-4 is restrained by the Bcl-2 homologue CED-9, Apaf-1 is inhibited by its WD40 repeat region, until it is activated by cytochrome c, derived from damaged mitochondria. Although Dark also has a WD40 region, its activation does not seem to involve cytochrome c. CED-4 is essential for apoptosis in the worm and Dark for many apoptotic responses in the fly, but the Apaf-1/caspase-9 system probably amplifies rather than initiates the mammalian caspase cascade.

Animals↗

PubMed2002

The Bcl2 family: regulators of the cellular life-or-death switch.

Tissue homeostasis is regulated by apoptosis, the cell-suicide programme that is executed by proteases called caspases. The Bcl2 family of intracellular proteins is the central regulator of caspase activation, and its opposing factions of anti- and pro-apoptotic members arbitrate the life-or-death decision. Apoptosis is often impaired in cancer and can limit conventional therapy. A better understanding of how the Bcl2 family controls caspase activation should result in new, more effective therapeutic approaches.

Animals↗