The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice

Adams, Jerry M.; Harris, Alan W.; Pinkert, Carl A.; Corcoran, Lynn M.; Alexander, Warren S.; Cory, Suzanne; Palmiter, Richard D.; Brinster, Ralph L.

doi:10.1038/318533a0

Cited by 1,665 publications

(1,381 citation statements)

References 53 publications

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“…This typical 'starry-sky' pattern was also seen in affected lymphoid organs of Em-myc; IL-7Ra þ /449F and Em-myc; IL-7Ra 449F animals in the majority of cases (data not shown; Figure 5a). In agreement with previous findings (Adams et al, 1985), Em-myc; IL-7Ra þ / þ tumors were composed of either pre-B or mature B cells, and this was also the case for the majority of the Em-myc; IL-7Ra 449F tumors (Supplementary Table 2). In addition, IL-7Ra 449F mutation did not affect the characteristic hyperproliferation induced by c-Myc in these end-stage tumors (data not shown).…”

Section: C-myc Tumors Retain Il-7 Responsiveness But Become Il-7 Indesupporting

confidence: 92%

“…This genetic analysis indicated that IL-7Ra signals involved in B lymphopoiesis were critical for the emergence of Em-myc-induced tumors. Overexpression of the c-Myc oncoprotein results in developmental arrest and pre-B-or B-cell lymphomas (Adams et al, 1985;Langdon et al, 1986). As IL-7Ra 449F mice have decreased numbers of peripheral B cells , it was possible the Em-myc; IL-7Ra 449F mice were protected from c-Myc-induced lymphomagenesis due to a decreased population of lymphoma precursors.…”

Section: Resultsmentioning

confidence: 99%

“…c-Myc is a transcription factor that has a key role in regulating B-lymphocyte differentiation and expansion (Habib et al, 2007). Overexpression of c-Myc in the Em-myc mouse causes transformation of pre-B cells (Adams et al, 1985) and is a well-defined model for human B lymphomagenesis. Similarly, transgenic overexpression of IL-7 (Tg IL-7) caused mixed T-and B-cell lymphomas that arose by oligoclonal expansion of variable subsets, which could form masses upon transfer to either immunocompetent or nude mice (Rich et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

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Selective ablation of the YxxM motif of IL-7Rα suppresses lymphomagenesis but maintains lymphocyte development

et al. 2010

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Tumor progression is a multiple step process in which, in addition to oncogenic mutation, other supporting factors can contribute to transformation. The role these factors have in cancer is an open question. Using the El-myc model of B-cell transformation, we evaluated the contribution of the cytokine interleukin-7 (IL-7) in supporting lymphomagenesis. We have previously shown that disruption of the Y449xxM motif of the IL-7 receptor alpha (IL-7Ra) in a knock-in mouse model (IL-7Ra 449F ) has minor effects on lymphocyte production, but interferes with the activation of survival effectors. To address the hypothesis that targeted signal ablation would selectively affect lymphocyte transformation, IL-7Ra 449F mice were crossed with two lymphomagenesis models, transgenic (Tg) IL-7 and El-myc mice. We found that the loss of IL-7Ra Y449 signaling prevented Tg IL-7-mediated T-and B-lymphocyte transformation and decreased the development of El-myc-induced B-cell tumors. We showed that the IL-7Ra 449F mutation prevented increased survival of Tg IL-7 CD8 T cells, and decreased viability of bone marrow progenitor B cells, as well as Elmyc-induced proliferation. This study shows that IL-7Ra Y449 is important for lymphocyte transformation, and that unlike deficiencies in pre-B cell receptor signaling, Myc overexpression cannot compensate for the loss of IL-7Ra signals in early B-cell development.

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Section: C-myc Tumors Retain Il-7 Responsiveness But Become Il-7 Indesupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Selective ablation of the YxxM motif of IL-7Rα suppresses lymphomagenesis but maintains lymphocyte development

et al. 2010

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“…MIF þ / þ p53 À/À (referred to as p53 À/À ) and MIF À/À p53 À/À (DKO) mice were derived from crosses between the double heterozygous animals. Wild-type, MIF À/À and p53 À/À mice (all 129Sv) were interbred with a C57Bl/6 strain of EmMyc transgenic mice 26,27 to obtain the F2 generations of MIF þ / þ , MIF þ /À , MIF À/À , and p53 þ /À transgenic animals. The genotype of mice was verified by PCR amplification specific for the corresponding Wild type (WT) and mutant alleles.…”

Section: Mice and Tissue Culturementioning

confidence: 99%

MIF loss impairs Myc-induced lymphomagenesis

et al. 2005

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Macrophage migration inhibitory factor (MIF) is a potent regulator of inflammation and cell growth. Using the El-Myc lymphoma mouse model, we demonstrate that loss of MIF markedly delays the onset of B-cell lymphoma development in vivo. The molecular basis for this MIF-loss-induced phenotype is the perturbed DNA-binding activity of E2F factors and the concomitantly enhanced tumor suppressor activity of the p53 pathway. Accordingly, premalignant MIF-null El-Myc Bcells are predisposed to delayed S-phase progression and increased apoptosis. MIF-deficient lymphomas that do arise under these conditions contain frequent ARF deletions and p53 inactivating mutations. Conversely, MIF expression is retained in tumors developed by wild-type El-Myc animals, and the presence of one or both MIF alleles is sufficient to accelerate the development of Myc-induced lymphomas. Collectively, these results indicate that MIF promotes Mycmediated tumorigenesis, at least in the B-lymphoid compartment, and implicate MIF as a mediator of malignant cell growth in vivo.

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“…Vav‐BCL2 37, Vav‐Mcl1 31, and Eμ‐MYC 48 mice were described previously. Vav‐BFL1 and Vav‐BCLX TG mice were generated by pronuclear injection of the VavP vectors 36 encoding human FLAG‐BFL1 or human FLAG‐BCLX cDNA into C57BL/6N oocytes.…”

Section: Methodsmentioning

confidence: 99%

Differential effects of Vav‐promoter‐driven overexpression of BCLX and BFL1 on lymphocyte survival and B cell lymphomagenesis

et al. 2018

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Overexpression of BCLX and BFL1/A1 has been reported in various human malignancies and is associated with poor prognosis and drug resistance, identifying these prosurvival BCL2 family members as putative drug targets. We have generated transgenic mice that express human BFL1 or human BCLX protein throughout the haematopoietic system under the control of the Vav gene promoter. Haematopoiesis is normal in both the Vav‐BFL1 and Vav‐BCLX transgenic (TG) mice and susceptibility to spontaneous haematopoietic malignancies is not increased. Lymphoid cells from Vav‐BCLX TG mice exhibit increased resistance to apoptosis in vitro while most blood cell types form Vav‐BFL1 TG mice were poorly protected. Both transgenes significantly accelerated lymphomagenesis in Eμ‐MYC TG mice and, surprisingly, the Vav‐BFL1 transgene was the more potent. Unexpectedly, expression of transgenic BFL1 RNA and protein is significantly elevated in B lymphoid cells of Vav‐BFL1/Eμ‐MYC double‐transgenic compared to Vav‐BFL1 mice, even during the preleukaemic phase, providing a rationale for the potent synergy. In contrast, Vav‐BCLX expression was not notably different. These mouse models of BFL1 and BCLX overexpression in lymphomas should be useful tools for the testing the efficacy of novel human BFL1‐ and BCLX‐specific inhibitors.

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The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice

Cited by 1,665 publications

References 53 publications

Selective ablation of the YxxM motif of IL-7Rα suppresses lymphomagenesis but maintains lymphocyte development

Selective ablation of the YxxM motif of IL-7Rα suppresses lymphomagenesis but maintains lymphocyte development

MIF loss impairs Myc-induced lymphomagenesis

Differential effects of Vav‐promoter‐driven overexpression of BCLX and BFL1 on lymphocyte survival and B cell lymphomagenesis

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