Abstract 5864: Genetic screens reveal dependencies and chemotherapy modulators in NSD2-driven hematologic malignancies

Abstract

Abstract The histone methyltransferase NSD2 contributes to the pathogenesis and chemoresistance of various hematologic cancers. In multiple myeloma (MM), NSD2 overexpression drives an oncogenic epigenetic and transcriptional program promoting clonogenicity, proliferation, altered adhesion and chemoresistance. Further, a gain-of-function mutation of NSD2 promotes oncogenic reprogramming and chemoresistance in acute lymphocytic leukemia (ALL). So far, attempts to develop specific and potent NSD2 inhibitors have not been successful. Here, we utilized genome-wide CRISPR-based loss-of-function genetic screens to explore molecular dependencies and modulators of chemotherapy response in hematologic malignancies with aberrant NSD2 activity. We assessed gene essentiality in KMS11-derived NSD2-high and NSD2-low isogenic MM cells. Differential essentiality analysis revealed multiple genes whose disruption is selectively detrimental in cells with NSD2 overexpression. These include the adenine nucleotide regulator Adenylate Kinase 2 (AK2) and the super elongation complex (SEC) component ELL-Associated Factor 1 (EAF1), which were validated by in vitro competition assays. We further found that NSD2-high cells exhibit higher dependency on the druggable anti-apoptotic factor BCL2 and demonstrated a stronger synergy between BCL2 inhibitors and the glucocorticoid dexamethasone in these cells compared to NSD2-low cells. This finding suggests that BCL2 inhibitors can be used to potentiate dexamethasone response in MM patients with t(4;14) chromosomal translocation, where NSD2 is overexpressed. We also utilized the CRISPR-based genetic approach to investigate cellular processes influencing sensitivity of NSD2-driven MM cells to dexamethasone. Our study identified multiple cellular pathways as modulators of dexamethasone response in MM. For example, we showed that the IL10-JAK-STAT pathway mediates dexamethasone resistance whereas certain components of mRNA degradation function as dexamethasone sensitizers. How these pathways and other uncovered key players alter MM cell response to dexamethasone is still under investigation. We previously demonstrated that an activating NSD2 mutation leads to dexamethasone resistance in ALL. We sought to explore the mechanisms by which mutant NSD2 drives dexamethasone resistance and the cellular processes that can be targeted to restore dexamethasone sensitivity in ALL cells. Genome-wide CRISPR screens in RCH-ACV, a dexamethasone-resistant B-ALL cell line harboring the NSD2 mutation, uncovered multiple modulators of dexamethasone response. Intriguingly, we found that disruption of any component of a transcriptional complex involving LMO2, LDB1 and LYL1 sensitizes RCH-ACV cells to dexamethasone. Targeting this complex could be relevant to overcoming dexamethasone resistance in relapsed pediatric ALL. Citation Format: Amin Sobh, Charlotte Kaestner, Alberto Riva, Jianping Li, Richard Bennett, Jonathan Licht. Genetic screens reveal dependencies and chemotherapy modulators in NSD2-driven hematologic malignancies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5864.