Oncogenic mechanisms and molecular targets in lymphoma

Division Of Basic Sciences - Nci

Investigators

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Abstract

We use CRISPR-Cas9 screens loss of function screens, together with quantitative proteomics and molecular imaging to identify new vulnerabilities in lymphoma model systems. In a study recently published in Cancer Cell, we used these methods to reveal the role for selective autophagy in degrading the mutant MYD88 L265P isoform that is responsible for assembly of a signaling super-complex, the My-T-BCR, the is required for survival of the MCD genetic subtype of DLBCL. We showed that ubiquitination of MYD88 and associated proteins is essential for this autophagic turnover and that blockade of oncogenic BCR signaling with BTK inhibitors promoted MYD88 ubiquitination and autophagic degradation. This finding illuminates the exceptional efficacy of BTK inhibitors in patients with MCD DLBCL, either as monotherapy or in combination with chemotherapy. We also used CRISPR-Cas9 screens to identify determinants of lymphoma sensitivity to Polatuzumab vedotin (Pola-V), an antibody-drug conjugate targeting the BCR subunit CD79B that was recently approved for the treatment of newly diagnosed DLBCL. We discovered that the addition of sialic acid to glycans attached to CD79B and another BCR subunit CD79A inhibited Pola-V binding, and that enzymatic or pharmacologic inhibition of BCR sialyation increased Pola-V efficacy 10-fold, resulting in improved control of DLBCL xenograft growth. Thus, sialylation inhibitors could be developed to enhance Pola-V clinical efficacy. Our functional screens further showed that loss of the E3 ubiquitin ligase KLHL6 sensitized GCB DLBCL cells to Pola-V binding. Proteomic analysis revealed that KLHL6 regulates the turnover of cell surface BCR by promoting ubiquitination of CD79B, thereby directly the BCR towards lysosomal degradation. KLHL6 is specifically upregulated in germinal center B cells, the cell-of-origin of GCB DLBCL, which offers an explanation for why Pola-V addition to chemotherapy was beneficial in ABC but not GCB DLBCL. Accordingly, we are currently evaluating the effect of Pola-V addition to the multi-targeted ViPOR regimen in patients with relapsed/refractory non-GCB DLBCL.