Data from An Autochthonous Mouse Model of <i>Myd88</i>- and <i>BCL2</i>-Driven Diffuse Large B-cell Lymphoma Reveals Actionable Molecular Vulnerabilities

Abstract

&lt;div&gt;Abstract&lt;p&gt;Based on gene expression profiles, diffuse large B-cell lymphoma (DLBCL) is subdivided into germinal center B-cell–like (GCB) and activated B-cell–like (ABC) DLBCL. Two of the most common genomic aberrations in ABC-DLBCL are mutations in &lt;i&gt;MYD88&lt;/i&gt; as well as &lt;i&gt;BCL2&lt;/i&gt; copy-number gains. Here, we employ immune phenotyping, RNA sequencing, and whole-exome sequencing to characterize a &lt;i&gt;Myd88&lt;/i&gt;- and BCL2-driven mouse model of ABC-DLBCL. We show that this model resembles features of human ABC-DLBCL. We further demonstrate an actionable dependence of our murine ABC-DLBCL model on BCL2. This BCL2 dependence was also detectable in human ABC-DLBCL cell lines. Moreover, human ABC-DLBCLs displayed increased &lt;i&gt;PD-L1&lt;/i&gt; expression compared with GCB-DLBCL. &lt;i&gt;In vivo&lt;/i&gt; experiments in our ABC-DLBCL model showed that combined venetoclax and PD-1 blockade significantly increased the overall survival of lymphoma-bearing animals, indicating that this combination may be a viable option for selected human ABC-DLBCL cases harboring &lt;i&gt;MYD88&lt;/i&gt; and &lt;i&gt;BCL2&lt;/i&gt; aberrations.&lt;/p&gt;Significance:&lt;p&gt;Oncogenic &lt;i&gt;Myd88&lt;/i&gt; and &lt;i&gt;BCL2&lt;/i&gt; cooperate in murine DLBCL lymphomagenesis. The resulting lymphomas display morphologic and transcriptomic features reminiscent of human ABC-DLBCL. Data derived from our &lt;i&gt;Myd88&lt;/i&gt;/&lt;i&gt;BCL2&lt;/i&gt;-driven autochthonous model demonstrate that combined BCL2 and PD-1 blockade displays substantial preclinical antilymphoma activity, providing preclinical proof-of-concept data, which pave the way for clinical translation.&lt;/p&gt;&lt;p&gt;&lt;i&gt;This article is highlighted in the In This Issue feature, p. 1&lt;/i&gt;&lt;/p&gt;&lt;/div&gt;