Insights from transgenic mice regarding the role of bcl -2 in normal and neoplastic lymphoid cells

1994 ◽  
Vol 345 (1313) ◽  
pp. 289-295 ◽  
Keyword(s):  
Transgenic Mice ◽  
Cell Survival ◽  
Lupus Erythematosus ◽  
Low Frequency ◽  
Rapid Onset ◽  
Chromosome Translocation ◽  
Lymphoid Cells ◽  
Cytotoxic Agents ◽  
B Lymphoid ◽  
The Impact

The bcl -2 gene was first discovered by molecular analysis of the 14; 18 chromosome translocation which is the hallmark of most cases of human follicular lymphoma. To date, it is unique among proto-oncogenes because, rather than promoting cell proliferation, it fosters cell survival. This review summarizes the impact of constitutive bcl -2 expression on the development and function of lymphocytes as well as their malignant transformation. Expression of a bcl -2 transgene in the B lymphoid compartment profoundly perturbed homeostasis and, depending on the genetic background, predisposed to a severe autoimmune disease resembling human systemic lupus erythematosus. T lymphoid cells from transgenic mice were remarkably resistant to diverse cytotoxic agents. Nevertheless, T lymphoid homeostasis was unaffected and tolerance to self was maintained. Expression of high levels of Bcl-2 facilitated the development of B lymphoid tumours but at relatively low frequency and with long latency. Co-expression of myc and bcl -2, on the other hand, promoted the rapid onset of novel tumours which appeared to derive from a lympho-myeloid stem or progenitor cell. Introduction of the bcl -2 transgene into scid mice facilitated the survival and differentiation of pro-B but not pro-T cells, suggesting that a function necessary to supplement or complement the action of Bcl-2 is expressed later in the T than the B lineage. Crosses of the bcl -2 transgenic mice with p53- /- mice have addressed whether loss of p53 function and gain of bcl -2 function are synergistic for lymphoid cell survival.

scholarly journals The Impact of Hyperosmolality on Activation and Differentiation of B Lymphoid Cells

2019 ◽  
Vol 10 ◽  
Author(s):  
Ljiljana Cvetkovic ◽  
Stojan Perisic ◽  
Jens Titze ◽  
Hans-Martin Jäck ◽  
Wolfgang Schuh
Keyword(s):  
Lymphoid Cells ◽  
B Lymphoid ◽  
The Impact

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

Blood ◽  
2004 ◽  
Vol 103 (6) ◽  
pp. 2276-2283 ◽  
Author(s):  
Alexander Egle ◽  
Alan W. Harris ◽  
Mary L. Bath ◽  
Lorraine O'Reilly ◽  
Suzanne Cory
Keyword(s):  
T Cells ◽  
Transgenic Mice ◽  
Follicular Lymphoma ◽  
Germinal Center ◽  
Cd4 T Cells ◽  
Chromosome Translocation ◽  
Regulatory Sequences ◽  
Germinal Center Hyperplasia ◽  
B Lymphoid

Abstract 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 (Eμ) 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 Eμ-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 Eμ-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.

scholarly journals Expression of the c-myc oncogene under control of an immunoglobulin enhancer in E mu-myc transgenic mice.

1987 ◽  
Vol 7 (4) ◽  
pp. 1436-1444 ◽  
Author(s):  
W S Alexander ◽  
J W Schrader ◽  
J M Adams
Keyword(s):  
Bone Marrow ◽  
Transgenic Mice ◽  
B Lymphocyte ◽  
Lymphoid Cells ◽  
Lymphoid Tissues ◽  
Myc Oncogene ◽  
Feedback Model ◽  
B Lymphocyte Development ◽  
B Lymphoid ◽  
Spleen And Lymph Nodes

Transgenic mice bearing a cellular myc oncogene coupled to the immunoglobulin heavy-chain enhancer (E mu) exhibit perturbed B-lymphocyte development and succumb to B lymphoid tumors. To investigate how the enhancer has affected myc expression, we analyzed the structure and abundance of myc transcripts in tissues of prelymphomatous mice and in the lymphomas. Expression of the E mu-myc transgene appeared to be confined largely to B lymphoid cells, being dominant in bone marrow, spleen, and lymph nodes, with no detectable expression in T cells or other hematopoietic lineages examined. The myc transcripts initiated very predominantly at the normal myc promoters, although use of the more upstream myc promoter was accentuated and an enhancer-associated promoter may be used infrequently. The level of E mu-myc transcripts in the preneoplastic lymphoid tissues and in the E mu-myc tumors was not markedly higher than myc RNA levels in proliferating normal lymphocytes. Thus, enforced expression of structurally normal myc transcripts at only a modestly elevated level has profound biological consequences. The absence of detectable endogenous c-myc RNA in any tumor, or in preneoplastic bone marrow, supports a negative feedback model for normal c-myc regulation.

JunB inhibits proliferation and transformation in B-lymphoid cells

Blood ◽  
2003 ◽  
Vol 102 (12) ◽  
pp. 4159-4165 ◽  
Author(s):  
Agnieszka P. Szremska ◽  
Lukas Kenner ◽  
Eva Weisz ◽  
Rene G. Ott ◽  
Emmanuelle Passegué ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
B Cell ◽  
Transgenic Animals ◽  
Inhibitory Effect ◽  
Lymphoid Cells ◽  
Negative Regulator ◽  
Transgenic Cells ◽  
B Lymphoid

Abstract The activator protein 1 (AP-1) member JunB has recently been implicated in leukemogenesis. Here we surveyed human lymphoma samples for expression of JunB and other AP-1 members (c-Jun, c-Fos, Fra1, JunD). JunB was strongly expressed in T-cell lymphomas, but non-Hodgkin B-cell lymphomas do not or only weakly express JunB. We therefore asked whether JunB acted as a negative regulator of B-cell development, proliferation, and transformation. We used transgenic mice that expressed JunB under the control of the ubiquitin C promoter; these displayed increased JunB levels in both B- and T-lymphoid cells. JunB transgenic cells of B-lymphoid, but not of T-lymphoid, origin responded poorly to mitogenic stimuli. Furthermore, JunB transgenic cells were found to be less susceptible to the transforming potential of the Abelson oncogene in vitro. In addition, overexpression of JunB partially protected transgenic mice against the oncogenic challenge in vivo. However, transformed B cells eventually escaped from the inhibitory effect of JunB: the proliferative response was similar in explanted tumor-derived cells from transgenic animals and those from wild-type controls. Our results identify JunB as a novel regulator of B-cell proliferation and transformation. (Blood. 2003;102:4159-4165)

Cytotoxic Injury to Thymic Stroma and Impaired Reconstitution.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1232-1232
Author(s):  
Susan E. Prockop ◽  
Richard J. O’Reilly ◽  
Howard Petrie
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
De Novo ◽  
Immunosuppressive Treatment ◽  
Lymphoid Cells ◽  
Cytotoxic Agents ◽  
Cell Transplant ◽  
Wild Type ◽  
Long Term Outcome ◽  
The Impact

Abstract A key component of long-term outcome after stem cell transplant (SCT) is successful reconstitution of the immune system. Effective reconstitution of antigen-specific T-cell immunity requires de novo T cell generation. Bone marrow derived progenitors seed the thymus and undergo a complex process involving lineage commitment, proliferation and selection. Coordinated interaction of marrow-derived lymphoid progenitors with thymic stromal cells is required for successful T lymphopoiesis in the post-natal thymus. Disruption of the microenvironment can result in disrupted T cell lymphopoiesis. One cause of prolonged defects in generating functional T lymphocytes after BMT is damage to the thymic microenvironment induced by radiation or cytotoxic therapy. However, the impact of individual agents, administered at myeloablative or non-myeloablative doses, on the thymic microenvironment has not been fully evaluated. In addition, mechanisms by which stromal injury modifies T cell production and maturation have only begun to be understood. We have developed a model system using immunodeficient mice as a platform on which to assess thymic reconstitution. The thymus of mice deficient for the alpha chain of the IL-7 receptor (IL7R−/−) is relatively depleted of lymphoid cells and can be reconstituted following transplant of wild type marrow administered without myeloablative or immunosuppressive treatment. Injection of low doses of wild type bone marrow into these mice results in low levels of marrow chimerism and a normally cellular thymus repopulated with donor-derived lymphocytes. The ability to achieve this reconstitution appears to depend on absolute numbers of early intra-thymic precursors, rather than on total thymic cellularity. We have exploited this model to differentially assess the effects of cytotoxic agents including radiation and immunosuppressive drugs, on the capacity of the thymic microenvironment to support the maturation of normal lympoid progenitors (Figure 1). We demonstrate that some agents do not affect the ability of the thymic microenvironment to support reconstitution (eg fludarabine), others nearly ablate it (cyclophosphamide). We are also able to show dose, schedule, and synergistic effects on the ability of the thymic microenvironment to support de novo T cell lymphopoeisis. Distinct morphologic and phenotypic effects can be demonstrated by different agents (eg busulfan versus thiotepa) with preliminary data suggesting that the effects are mediated by injury to different stromal subsets. It is anticipated that this information will lead to strategies to both minimize delayed immune reconstitution and to augment T cell lymphopoiesis post-transplant. In addition, further evaluation of impaired thymic reconstitution will augment the understanding of lymphostromal interactions crucial to normal T cell lymphopoiesis.

scholarly journals Endogenous Bcl-xL is essential for Myc-driven lymphomagenesis in mice

Blood ◽  
2011 ◽  
Vol 118 (24) ◽  
pp. 6380-6386 ◽  
Author(s):  
Priscilla N. Kelly ◽  
Stephanie Grabow ◽  
Alex R. D. Delbridge ◽  
Andreas Strasser ◽  
Jerry M. Adams
Keyword(s):  
Cell Death ◽  
Transgenic Mice ◽  
Family Members ◽  
Lymphoid Cells ◽  
Close Relative ◽  
B Lymphoma ◽  
Normal Expression ◽  
B Lymphoid ◽  
Bh3 Mimetic ◽  
Striking Contrast

Abstract Impaired apoptosis is a cancer hallmark, and some types of lymphomas and other cancers harbor mutations that directly affect key cell death regulators, such as Bcl-2 family members. However, because the majority of tumors seem to lack such mutations, we are examining the hypothesis that tumorigenesis can be sustained at least initially by the normal expression of specific endogenous pro-survival Bcl-2 family members. We previously demonstrated that the lymphomagenesis in Εμ-myc transgenic mice, which constitutively overexpress the c-Myc oncoprotein in B-lymphoid cells and develop pre-B and B-cell lymphomas, does not require endogenous Bcl-2. In striking contrast, we report here that loss in these mice of its close relative Bcl-xL attenuated the pre-neoplastic expansion of pro-B and pre-B cells otherwise driven by c-Myc overexpression, sensitized these cells to apoptosis and ablated lymphoma formation. Remarkably, even loss of a single bcl-x allele delayed the lymphomagenesis. These findings identify Bcl-xL as a prerequisite for the emergence of c-Myc–driven pre-B/B lymphoma and suggest that BH3 mimetic drugs may provide a prophylactic strategy for c-Myc–driven tumors.

Expression of the c-myc oncogene under control of an immunoglobulin enhancer in E mu-myc transgenic mice

1987 ◽  
Vol 7 (4) ◽  
pp. 1436-1444
Author(s):  
W S Alexander ◽  
J W Schrader ◽  
J M Adams
Keyword(s):  
Bone Marrow ◽  
Transgenic Mice ◽  
B Lymphocyte ◽  
Lymphoid Cells ◽  
Lymphoid Tissues ◽  
Myc Oncogene ◽  
Feedback Model ◽  
B Lymphocyte Development ◽  
B Lymphoid ◽  
Spleen And Lymph Nodes

Transgenic mice bearing a cellular myc oncogene coupled to the immunoglobulin heavy-chain enhancer (E mu) exhibit perturbed B-lymphocyte development and succumb to B lymphoid tumors. To investigate how the enhancer has affected myc expression, we analyzed the structure and abundance of myc transcripts in tissues of prelymphomatous mice and in the lymphomas. Expression of the E mu-myc transgene appeared to be confined largely to B lymphoid cells, being dominant in bone marrow, spleen, and lymph nodes, with no detectable expression in T cells or other hematopoietic lineages examined. The myc transcripts initiated very predominantly at the normal myc promoters, although use of the more upstream myc promoter was accentuated and an enhancer-associated promoter may be used infrequently. The level of E mu-myc transcripts in the preneoplastic lymphoid tissues and in the E mu-myc tumors was not markedly higher than myc RNA levels in proliferating normal lymphocytes. Thus, enforced expression of structurally normal myc transcripts at only a modestly elevated level has profound biological consequences. The absence of detectable endogenous c-myc RNA in any tumor, or in preneoplastic bone marrow, supports a negative feedback model for normal c-myc regulation.

scholarly journals Two Distinct Interleukin-3-Mediated Signal Pathways, Ras-NFIL3 (E4BP4) and Bcl-xL, Regulate the Survival of Murine Pro-B Lymphocytes

1999 ◽  
Vol 19 (4) ◽  
pp. 2754-2762 ◽  
Author(s):  
Ryoko Kuribara ◽  
Taisei Kinoshita ◽  
Atsushi Miyajima ◽  
Tetsuharu Shinjyo ◽  
Takao Yoshihara ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Cell Survival ◽  
Cell Fate ◽  
Lymphoid Cells ◽  
Mitogen Activated Protein Kinase ◽  
Signal Transduction Pathways ◽  
Signal Pathways ◽  
Interleukin 3 ◽  
Mitogen Activated Protein ◽  
B Lymphoid

ABSTRACT Hematopoietic cells require cytokine-initiated signals for survival as well as proliferation. The pathways that transduce these signals, ensuring timely regulation of cell fate genes, remain largely undefined. The NFIL3 (E4BP4) transcription factor, Bcl-xL, and constitutively active mutants of components in Ras signal transduction pathways have been identified as key regulation proteins affecting murine interleukin-3 (IL-3)-dependent cell survival. Here we show that expression of NFIL3 is regulated by oncogenic Ras mutants through both the Raf–mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways. NFIL3 inhibits apoptosis without affecting Bcl-xL expression. By contrast, Bcl-xL levels are regulated through the membrane proximal portion in the cytoplasmic domain of the receptor (βc chain), which is shared by IL-3 and granulocyte-macrophage colony-stimulating factor. Activation of either pathway alone is insufficient to ensure cell survival, indicating that multiple independent signal transduction pathways mediate the survival of developing B-lymphoid cells.

Development of a Blastoid Variant, Mantle Cell Lymphoma Model in Transgenic Mice.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 419-419
Author(s):  
Richard J. Ford ◽  
Yen-Chiu Lin-Lee ◽  
Long Shen ◽  
Connie Xu ◽  
Chongjie Zhang ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
B Cell ◽  
Mantle Cell Lymphoma ◽  
B Lymphocytes ◽  
Cell Lymphoma ◽  
Lymphoid Cells ◽  
Mantle Cell ◽  
B Lymphoid ◽  
Hodgkin's Lymphomas

Abstract Mantle Cell Lymphoma (MCL) is a poorly understood, aggressive histotype of B-cell non-Hodgkin’s Lymphomas (NHL-B) that remains the most therapeutically resistant of the NHL-B. Little is known regarding why MCL is so clinically aggressive and therapeutically refractory. Blastoid variant MCL (MCL-BV) is an even more aggressive form of MCL that appears to be increasing in incidence in the US. It may represent progression from classic MCL, often with leukemic involvement and complex lymphoma karyotypes. Interleukin 14 (IL-14) is cytokine that was identified and cloned from a Burkitt lymphoma (BL) cell line that acts as a growth factor for normal B-lymphocytes. The expression of IL-14a protein and mRNA levels are elevated at lease fifty-fold in B-cell non-Hodgkin’s Lymphomas (NHL-B), including mantle cell lymphoma (MCL), in contrast to very low levels of IL-14a in quiescent (Go) B cells by both western and northern blot analysis. To evaluate the role of IL-14 in vivo, we have generated transgenic mice expressing IL-14 with pEuSR. The IL-14 TG mice generally live a normal life span, however when autopsies are performed at 18 months of age, splenomegaly is noted, and 50% have evidence of B cell lymphoma. This lymphoma is CD5+, CD19+, sIgM+, CD21− and contains a monoclonal population of B-lymphocytes with rearranged immunoglobulin genes. Morphologically the lymphoma arising in IL-14 transgenic mice resembles the centroblastic/Immunoblastic histotype of DLBCL. Because of the frequent involvement of c-myc in various B cell malignancies, we crossed Eμ-myc (c-myc TG) mice with the IL-14 TG mice. By 3 months of age, 100% of the double transgenic (DTG) mice develop an aggressive B cell malignancy that is characterized by extensive lymphadenopathy and splenomegaly with intermediate to large atypical lymphoid cells, strongly resembling MCL-BV morphologically. This tumor, like that derived from the IL-14 TG mice, is CD5+, CD19+, sIgM+, CD21−. It is also CD23− and over-expresses Cyclin D1 in monoclonal B lymphoid cells with re-arranged IgH immunoglobulin genes, mimicking the MCL phenotype. At the time of autopsy, tumor infiltration of DTG mice is generally found in all organs evaluated, including peripheral blood, lymph nodes, spleen, liver, bone marrow, thymus and kidneys, consistent with the usual findings in MCL-BV. No tumors are observed in IL-14α TG or c-myc TG mice autopsied at this age. This MCL-BV model allows for the molecular and genotypic characterization of the murine B lymphoid cell compartment from birth to lymphoma development (3 mos.), including histogenesis and functional determination of the growth and survival characteristics of these tumors in DTG bone marrow and peripheral B cell populations. Preliminary comparative in vitro and in vivo (SCID Xeno-transplants) studies in DTG/MCL-BV lymphomas have shown additional molecular similarities to the pathophysiology (e.g constitutive NF-kB activation) of MCL-BV cell lines and patient samples, that should provide insights for future potential therapeutic approaches to MCL.

Leukemic Hierarchy and Systemic Factors Dictating Disease Evolution In Chronic Myelogenous Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 886-886
Author(s):  
Damien Reynaud ◽  
Eric Pietras ◽  
Marion Jeanne ◽  
Keegan Barry-Holson ◽  
Emmanuelle Passegue
Keyword(s):  
Stem Cells ◽  
Chronic Myelogenous Leukemia ◽  
Conflicts Of Interest ◽  
Blast Crisis ◽  
Lymphoid Cells ◽  
Myelogenous Leukemia ◽  
Hematopoietic Stem ◽  
Disease Evolution ◽  
B Lymphoid ◽  
The Impact

Abstract Abstract 886 Chronic myelogenous leukemia (CML) is a clonal myeloproliferative neoplasm (MPN) characterized by the t(9;22)(q34;q11) reciprocal translocation, which leads to the expression of the BCR/ABL fusion protein. CML is clinically characterized by the abnormal expansion of the myeloid lineage leading to progressive peripheral neutrophilia. This indolent disease has the propensity to evolve into an acute leukemia-like blastic phase involving either myeloid or B lymphoid cells. As such, CML constitutes a paradigm for understanding cellular and molecular events controlling chronic diseases and their evolution toward frank leukemia. CML arise from a small pool of leukemic stem cells (LSC) that can be operationally defined by their ability to sustain tumor growth over time and to transplant leukemia to recipient mice. Multiple lines of evidence indicate that LSCs originate from abnormally behaving hematopoietic stem cells (HSCs), although it is still largely unknown how BCR/ABL affects the biology of HSCs and the fate of downstream progenitor cells. To study the impact of BCR/ABL expression on these compartments, we used a transgenic mouse model that allows for inducible expression of BCR/ABL in HSCs and downstream progeny (Blood 105: 324, 2005). Induction of BCR/ABL expression in this model recapitulated many features of human CML such as myeloid bone marrow (BM) hyperplasia, myelofibrosis, splenomegaly and myeloid cell infiltration in non-hematopoietic organs. Disease development also correlated with a dramatic reorganization of the stem and progenitor compartments in the BM and their relocation/expansion in the spleen. In the BM, we observed a marked reduction in the number of Lin– Sca1+ c-Kit+ Flk2– CD48– CD150+ long-term (LT) and Lin– Sca1+ c-Kit+ Flk2– CD48– CD150– short-term (ST) HSCs associated with an expansion of several types of non-self-renewing multipotent progenitors (MPP) and myeloid committed progenitors. We confirmed by limited dilution transplantation experiments that BCR/ABL+ LT-HSCs were true LSCs as they were the only cells capable of transferring sustained CML disease in recipient mice with as few as 50 cells injected. We also found that BCR/ABL expression impacts on the biology of the ST-HSC and Lin– Sca1+ c-Kit+ Flk2+ MPP compartments. Transplantation of both populations induced dramatic but transient hyperplasia, which could eventually mimic a leukemic phenotype with high doses of cell injected (4,000 cells per mouse). However, while transplantation of BCR/ABL+ ST-HSCs led to the expected myeloid hyperplasia, transplantation of BCR/ABL+ MPPs led to a massive accumulation of B-cell progenitors in the BM that resembles lymphoid blast crisis. Strikingly, co-transplantation of 4,000 BCR/ABL+ LT- or ST-HSCs with 4,000 BCR/ABL+ MPPs almost always resulted in myeloid hyperplasia suggesting an active inhibition of MPP-derived lymphoid progeny by the leukemic myeloid compartment. We reasoned that the molecular effectors for this lymphoid inhibitory effect could be extracellular signaling molecules that will be detectable in the serum of CML-developing BCR/ABL mice. Using antibody arrays and enzyme-linked immunosorbent assays (ELISA), we found that the serum concentration of the proinflammatory cytokine interleukine-6 (IL-6) correlates with CML progression both in primary and transplanted mice. Moreover, we showed in vitro that IL-6 controls lineage fate decision of leukemic progenitors by promoting myeloid differentiation from MPPs at the expense of the B lymphoid lineage differentiation. As such, IL-6 targets both normal and malignant MPPs thereby providing a positive feedback loops that promote CML development. In summary, our results identify and functionally characterize a pathological hierarchy in CML that includes LSC and immature leukemic progenitors. They uncover a novel fate-regulatory mechanism at the systemic level that controls the differentiation outcome of the leukemic progenitors and can have key implication for disease progression. Taken together, they demonstrate that CML evolution is the result of a balance between BCR/ABL cell intrinsic effects and environmental cues and provide a rational for the paradoxical myeloid-lymphoid conversion that can be observed during lymphoid blast crisis. Disclosures: No relevant conflicts of interest to declare.

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