Martin Peifer / H Christian Reinhardt - A 9

Exploring actionable cooperating lesions that drive Myd88-mediated lymphomagenesis

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Oncogenic MYD88 mutations occur in 39% of all human activated B cell-type diffuse large B cell lymphoma (ABC-DLBCL). Data from human patients and our mouse models of Myd88-driven ABC-DLBCL indicate that Myd88 mutations cooperate with additional genomic aberrations in ABC-DLBCL lymphomagenesis. MYD88 is a difficult drug target. Thus, we propose to search for potentially druggable mutations that cooperate with oncogenic MYD88 in ABC-DLBCL lymphomagenesis. In addition, we propose to pursue a candidate approach for targeting MYD88-driven ABC-DLBCL in vivo, using IRAK4 inhibitors. Overall, we formulate three Specific Aims:

  • Aim 1:    Use genome sequencing, in order to reconstruct clonal
                     evolution of Myd88-driven   ABC-DLBCL
  • Aim 2:    Use an in vivo insertional mutagenesis screen to identify
                     genomic aberrations   that cooperate with oncogenic Myd88
  • Aim 3:    Explore pharmacologic repression of IRAK4 and BCL2,
                     as a therapeutic approach for Myd88-driven ABC-DLBCL

These Aims test the hypotheses that 1) oncogenic MYD88 cooperates with additional recurrent genomic aberrations in ABC-DLBCL, 2) insertional mutagenesis in vivo will reveal the identity of novel genomic aberrations that contribute to ABC-DLBCL lymphomagenesis and 3) that oncogenically rewired pathways downstream of oncogenic MYD88 might serve as targets for the personalized treatment of MYD88-driven ABC-DLBCL. ABC-DLBCL is a clinically difficult to treat entity. Our work may reveal potentially druggable molecular liabilities that are enriched in MYD88-mutant ABC-DLBCL.

Clinical/medical relevance and sustainability in disease understanding

We will employ a translational approach involving genome and transcriptome sequencing of a novel mouse model of Myd88-driven activated B cell-type diffuse large B cell lymphoma (ABC-DLBCL), to identify actionable genomic aberrations that cooperate with Myd88 in ABC-DLBCL lymphomagenesis. We combine this approach with an in vivo insertional mutagenesis screen, resequencing of human ABC-DLBCL, as well as a candidate approach to identify novel treatment regimens for this difficult to treat disease.

Selected publications

1. Knittel G, Rehkämper T, Korovkina D,..., Peifer M, Büttner R, Presigehl T, Reinhardt HC. Two mouse models reveal an actionable PARP1 dependence in aggressive chronic lymphocytic leukemia. Nature Communications (in press).
2. Schmitt A, Knittel G, Welcker D,...,Peifer M, Reinhardt HC. ATM Deficiency Is Associated with Sensitivity to PARP1- and ATR Inhibitors in Lung Adenocarcinoma. Cancer Research, 2017 77:3040-56.
3. Knittel G, Liedgens P, Korovkina D,...,Reinhardt HC. B-cell-specific conditional expression of Myd88p.L252P leads to the development of diffuse large B-cell lymphoma in mice. Blood, 2016 127:2732-41.
4. Peifer M*, Hertwig F, Roels F,..., Fischer M*. Telomerase activation by genomic rearrangements in high-risk neuroblastoma. Nature, 2015 52:700-4. *corresponding authors
5. George J, Lim JS, Jang SJ,...,Reinhardt HC,..., Peifer M*, Sage J*, Thomas RK*: Comprehensive genomic profiling of small cell lung cancer. Nature, 2015 524:47-53. *corresponding authors
6. Dietlein F, Kalb B, Jokic M,..., Reinhardt HC. A Synergistic Interaction between Chk1- and MK2 Inhibitors in KRAS-Mutant Cancer. Cell, 2015 162:146-59.

Prof. Dr. Martin Peifer

Dept. of Translational Genomics / RG location - CMMC Building

Prof. Dr. Martin Peifer

Principal Investigator A 9 / CAP 6

Work +49 221 478 96863

Fax (Work) +49 221 478 97902

Center for Moelcular Medicine Cologne (CMMC)
Robert-Koch-Str. 21
50931 Cologne

Publications - Martin Peifer

Link to PubMed

Prof. Dr. H Christian Reinhardt

Dept. I of Internal Medicine / RG location - Dept. of Translational Genomics

Prof. Dr. H Christian Reinhardt

Co-Principal Investigator A 9
Executive Board Member

Work +49 221 478 96701

Fax (Work) +49 221 478 97835

Cologne Center of Genomincs (CCG)
Weyertal 115 b
50931 Cologne

Publications - H Christian Reinhardt

Link to PubMed

Group Members

Nima Abedpour (PostDoc)
Maria Cartolano
Sebastian Klein
Tsun-Po Yang (doctoral student)