2019 - Covalent menin inhibitor, BMF-219, impacts key gene signatures and molecular pathways in Chronic Lymphocytic Leukemia patient-derived models

Chronic lymphocytic Leukemia (CLL) is the most common type of adult leukemia characterized by clonal proliferation of malignant B-lymphocytes. Although standard-of-care agents are well tolerated in CLL, patients with certain genetic subsets of the disease continue to display poor response to these therapeutic regimens. Menin is an epigenetic protein that drives oncogenic function through transcriptional regulation directed by interactions with various protein partners. In the B-cell maturation pathway, menin regulates a distinct set of genes targets (Li et al., 2013).

We previously described the potent activity of BMF-219, a selective covalent oral menin inhibitor, against a diverse panel of CLL patient specimens with various cytogenetic and mutational backgrounds, including TP53 and NOTCH1 mutations. We also reported the ability of BMF-219 to downregulate the anti-apoptotic gene, BCL2, an established major driver of CLL, in acute leukemia cells. Here, we provide insights into the molecular impact of BMF-219 in CLL patient samples, as revealed through gene expression profiling of CLL specimens from BTK-inhibitor experienced patients that represent clinical profiles of TP53 mutated and complex cytogenetic backgrounds (del13q, del6q).

BMF-219 displayed on-target activity through dose dependent reduction of the target gene, MEN1, in the treated patient samples. Differential gene expression analysis revealed alteration of additional novel gene targets, including reduction of BCL2 and genes modulated in response to prior BTK-inhibitor treatment. Gene set enrichment analysis highlighted top altered molecular pathways in BMF-219 treated CLL models. Notably, cell adhesion, cytokine receptor signaling, and autoimmune function were top downregulated pathways in BMF-219 treated CLL patient samples. Gene ontology analysis of biological processes and molecular function identified additional novel mechanisms elicited by BMF-219 in these treated CLL models. Furthermore, we provide new data demonstrating the superior potency of BMF-219 and ability to achieve >98% growth inhibition in ex vivo cultured CLL patient specimens when compared to new investigational drugs currently in clinical development and established standard-of-care agents for CLL.

Collectively, these data demonstrate the mechanistic impact of BMF-219 on key gene targets and molecular pathways modulated by covalent menin inhibition, further highlighting its potential as a novel therapeutic agent in CLL.