The cooperating mutation or “second hit” determines the immunologic visibility toward MYC-induced murine lymphomas

Schuster, Christian; Berger, Angelika; Hoelzl, Maria A.; Putz, Eva Maria; Frenzel, Anna; Simma, Olivia; Moritz, Nadine; Hoelbl, Andrea; Kovacic, Boris; Freissmuth, Michael; Müller, Mathias; Villunger, Andreas; Müllauer, Leonhard; Schmatz, Ana-Iris; Streubel, Berthold; Porpaczy, Edit; Jäger, Ulrich; Stoiber, Dagmar; Sexl, Veronika

doi:10.1182/blood-2010-10-313098

Cited by 31 publications

(44 citation statements)

References 48 publications

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“…cHL cells in our patient expressed Bcl-2 ( Figure 3G), possibly reflecting impaired immunological sculpting. [17][18][19] In summary, the present patient suggests the possibility of an association of hypomorphic STXBP2 mutations with lymphoma. The cumulative dose of etoposide received during HLH-therapy was low (0.2 g/m 2 ).…”

Section: Resultsmentioning

confidence: 52%

“…Quantification of EBV in serum revealed only 50-500 copies/mL. One course of standard adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy resulted in complete remission, as documented clinically and by 18 F-FDG-PET. The patient completed four courses of ABVD and local radiotherapy, followed by allogeneic hematopoietic stem cell transplantation (HSCT).…”

Section: Resultsmentioning

confidence: 95%

“…Of note, mouse models indicate tumor immunogenicity is dictated by oncogene expression. 17,18 Whereas overexpression of Myc or loss of p53 does not confer immunogenicity, overexpression of Bcl-2 does. cHL cells in our patient expressed Bcl-2 ( Figure 3G), possibly reflecting impaired immunological sculpting.…”

Section: Resultsmentioning

confidence: 99%

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Development of classical Hodgkin's lymphoma in an adult with biallelic STXBP2 mutations

et al. 2012

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Section: Resultsmentioning

confidence: 52%

Section: Resultsmentioning

confidence: 95%

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Development of classical Hodgkin's lymphoma in an adult with biallelic STXBP2 mutations

et al. 2012

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“…Intriguingly, our Eμ‐MYC/Vav‐BCLX DT mice developed mainly IgM + B cell lymphomas, like Eμ‐MYC mice lacking BIM 45 or BMF 46. It has been reported that Eμ‐MYC ‐driven IgM − immature B lymphomas are more aggressive and develop faster than their IgM + counterparts 30. This observation would be consistent with the prolonged tumour‐latency observed for Eμ‐MYC/Vav‐BCLX DT mice compared to Eμ‐MYC/Vav‐BFL1 DT mice that only develop IgM − tumours.…”

Section: Discussionmentioning

confidence: 56%

“…Stem/progenitor cell lymphomas also dominated in Eμ‐BCL2/Eμ‐MYC DT, Eμ‐Bclx/Eμ‐MYC DT and Vav‐Mcl1/Eμ‐MYC DT mice 29, 31, 32, while Vav‐BCL2/Eμ‐MYC DT mice developed IgM − CD19 + CD43 + pro‐B cell tumours 30. Interestingly, WBC counts were massively increased in premalignant Eμ‐MYC/Vav‐BFL1 DT mice compared to Eμ‐MYC TG littermate controls or age‐matched Eμ‐MYC/Vav‐BCLX DT mice.…”

Section: Discussionmentioning

confidence: 98%

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 prognosis of MYC translocation positive diffuse large B‐cell lymphoma depends on the second hit

Clipson

Barrans

Zeng

et al. 2015

The Journal of Pathology CR

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A proportion of MYC translocation positive diffuse large B‐cell lymphomas (DLBCL) harbour a BCL2 and/or BCL6 translocation, known as double‐hit DLBCL, and are clinically aggressive. It is unknown whether there are other genetic abnormalities that cooperate with MYC translocation and form double‐hit DLBCL, and whether there is a difference in clinical outcome between the double‐hit DLBCL and those with an isolated MYC translocation. We investigated TP53 gene mutations along with BCL2 and BCL6 translocations in a total of 234 cases of DLBCL, including 81 with MYC translocation. TP53 mutations were investigated by PCR and sequencing, while BCL2 and BCL6 translocation was studied by interphase fluorescence in situ hybridization. The majority of MYC translocation positive DLBCLs (60/81 = 74%) had at least one additional genetic hit. In MYC translocation positive DLBCL treated by R‐CHOP (n = 67), TP53 mutation and BCL2, but not BCL6 translocation had an adverse effect on patient overall survival. In comparison with DLBCL with an isolated MYC translocation, cases with MYC/TP53 double‐hits had the worst overall survival, followed by those with MYC/BCL2 double‐hits. In MYC translocation negative DLBCL treated by R‐CHOP (n = 101), TP53 mutation, BCL2 and BCL6 translocation had no impact on patient survival. The prognosis of MYC translocation positive DLBCL critically depends on the second hit, with TP53 mutations and BCL2 translocation contributing to an adverse prognosis. It is pivotal to investigate both TP53 mutations and BCL2 translocations in MYC translocation positive DLBCL, and to distinguish double‐hit DLBCLs from those with an isolated MYC translocation.

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The cooperating mutation or “second hit” determines the immunologic visibility toward MYC-induced murine lymphomas

Cited by 31 publications

References 48 publications

Development of classical Hodgkin's lymphoma in an adult with biallelic STXBP2 mutations

Development of classical Hodgkin's lymphoma in an adult with biallelic STXBP2 mutations

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

The prognosis of MYC translocation positive diffuse large B‐cell lymphoma depends on the second hit

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