Biology subjects

Bomben, R.

Publications and source records attributed to Bomben, R..

2 recordsLinked to original sources

bioRxiv2024

B cell receptor silencing reveals the origin of high-grade B cell lymphomas with MYC and BCL2 rearrangements

The B cell receptor (BCR) is essential for mature B cell lymphomas, serving as therapeutic target. Here, we show that high-grade B cell lymphomas with MYC and BCL2 rearrangements (HGBCL-DH-BCL2) predominantly exhibit immunoglobulin heavy (IGH) chain silencing, leading to BCR shutdown. HGBCL-DH-BCL2 with undetectable IGH (IGHUND) differ from IGH-expressing counterparts for germinal center-zone gene programs, MYC expression and T cell infiltration. While IGH+ HGBCL-DH-BCL2 prefer IGM/IG-Kappa expression, IGHUND counterparts have completed IGH class-switching, favoring IG-Lambda (IGL) light chains. IGHUND HGBCL-DH-BCL2 preserve IGHV gene integrity, overcoming antigen-driven selection. IGH silencing precedes onset and shapes evolution of HGBCL-DH-BCL2 from Follicular Lymphoma (FL) or FL/HGBCL-DH-BCL2 common precursor. In FL/HGBCL-DH-BCL2 pairs and HGBCL-DH-BCL2 models, BCR silencing promoted RAG1/2-dependent IG light chain editing, causing t(8;22)(q24;q11)/IGL::MYC. IGH silencing protected HGBCL-DH-BCL2 models from killing by CD79B-targeting Polatuzumab-Vedotin. Collectively, HGBCL-DH-BCL2 primarily originate from BCR-silenced isotype-switched t(14;18)/IGH::BCL2-positive (pre)FL cells acquiring IGL::MYC translocations during IG light chain revision, with clinical implications. SignificanceThese findings link BCR silencing in isotype-switched t(14;18)+ Follicular Lymphoma cells (or their precursors) to RAG1/2 re-expression, promoting IGL::MYC translocations responsible for transformation into high-grade B cell lymphomas (HGBCL). Predominant silencing of the BCR complex in HGBCL with MYC and BCL2 rearrangements protects tumor cells from CD79B-directed Polatuzumab-Vedotin killing.

cancer biology↗

bioRxiv2022

Proteogenomics refines the molecular classification of chronic lymphocytic leukemia

Cancer heterogeneity at the proteome level may explain differences in therapy response and prognosis beyond the currently established genomic and transcriptomic based diagnostics. The relevance of proteomics for disease classifications remains to be established in clinically heterogeneous cancer entities such as chronic lymphocytic leukemia (CLL). Here, we characterized the proteome and transcriptome in-depth alongside genetic and ex-vivo drug response profiling in a clinically well annotated CLL discovery cohort (n= 68). Unsupervised clustering of the proteome data revealed six subgroups. Five of these proteomic groups were associated with genetic features, while one group was only detectable at the proteome level. This new group was characterized by accelerated disease progression, high spliceosomal protein abundances associated with aberrant splicing, and low B cell receptor signaling protein abundances (ASB-CLL). We developed classifiers to identify ASB-CLL based on its characteristic proteome or splicing signature in two independent cohorts (n= 165, n= 169) and confirmed that ASB-CLL comprises about 20 % of CLL patients. The inferior overall survival observed in ASB-CLL was independent of both TP53- and IGHV mutation status. Our multi-omics analysis refines the classification of CLL and highlights the potential of proteomics to improve cancer patient stratification beyond genetic and transcriptomic profiling. Single sentence summaryWe performed the largest proteogenomic analysis of CLL, linked proteomic profiles to clinical outcomes, and discovered a new poor outcome subgroup (ASB-CLL).

cancer biology↗