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  Distinct genetically-determined origins of Myd88/Bcl2-driven aggressive lymphoma rationalize targeted therapeutic intervention strategies

Flümann, R., Hansen, J., Pelzer, B. W., Nieper, P., Lohmann, T., Kisis, I., et al. (2022). Distinct genetically-determined origins of Myd88/Bcl2-driven aggressive lymphoma rationalize targeted therapeutic intervention strategies. Blood Cancer Discov. doi:10.1158/2643-3230.BCD-22-0007.

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Flümann, R.1, Author           
Hansen, J.1, Author           
Pelzer, B. W., Author
Nieper, P., Author
Lohmann, T., Author
Kisis, I., Author
Riet, T., Author
Kohlhas, V., Author
Nguyen, P. H., Author
Peifer, M., Author
Abedpour, N., Author
Bosco, G., Author
Thomas, R. K., Author
Kochanek, M., Author
Knufer, J., Author
Jonigkeit, L., Author
Beleggia, F., Author
Holzem, A., Author
Buttner, R., Author
Lohneis, P., Author
Meinel, J., AuthorOrtmann, M., AuthorPersigehl, T., AuthorHallek, M., AuthorCalado, D. P., AuthorChmielewski, M., AuthorKlein, S., AuthorGothert, J. R., AuthorChapuy, B., AuthorZevnik, B., AuthorWunderlich, F. T., Authorvon Tresckow, B., AuthorJachimowicz, R. D.1, Author           Melnick, A. M., AuthorReinhardt, H. C., AuthorKnittel, G., Author more..
Affiliations:
1Jachimowicz – Mechanisms of DNA Repair, Max Planck Research Groups, Max Planck Institute for Biology of Ageing, Max Planck Society, ou_3394003              

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 Abstract: Genomic profiling revealed the identity of at least 5 subtypes of DLBCL, including the MCD/C5 cluster characterized by aberrations in MYD88, BCL2, PRDM1 and/or SPIB. We generated mouse models harboring B cell-specific Prdm1 or Spib aberrations on the background of oncogenic Myd88 and Bcl2 lesions. We deployed whole exome sequencing, transcriptome, flow- and mass cytometry analyses to demonstrate that Prdm1- or Spib-altered lymphomas display molecular features consistent with pre-memory B cells and light zone B cells, whereas lymphomas lacking these alterations were enriched for late light-zone and plasmablast-associated gene sets. Consistent with the phenotypic evidence for increased B cell receptor signaling activity in Prdm1-altered lymphomas, we demonstrate that combined BTK/BCL2 inhibition displays therapeutic activity in mice and in five out of six relapsed/refractory DLBCL patients. Moreover, Prdm1-altered lymphomas were immunogenic upon transplantation into immuno-competent hosts, displayed an actionable PD-L1 surface expression and were sensitive to anti-murine-CD19-CAR-T cell therapy, in vivo.

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 Dates: 2022-11-082022-11-08
 Publication Status: Issued
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 Identifiers: Other: 36346827
DOI: 10.1158/2643-3230.BCD-22-0007
ISSN: 2643-3249 (Electronic)2643-3230 (Linking)
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Title: Blood Cancer Discov
Source Genre: Journal
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