Abstract
B-cell receptor (BCR)-dependent signaling is central for leukemia B-cell homeostasis, as underscored by the promising clinical results obtained in patients with chronic lymphocytic leukemia (CLL) treated with novel agents targeting components of this pathway. Herein, we demonstrate that the mithralog EC-7072 displays high ex vivo cytotoxic activity against leukemia cells from CLL patients independently from high-risk prognostic markers and IGHV mutational status. EC-7072 was significantly less toxic against T cells and NK cells and did not alter the production of the immune effector molecules IFN-γ and perforin. EC-7072 directly triggered caspase-3-dependent CLL cell apoptosis, which was not abrogated by microenvironment-derived factors that sustain leukemia cell survival. RNA-sequencing analyses revealed a dramatic EC-7072-driven reprograming of the transcriptome of CLL cells, including a wide downregulation of multiple components and targets of the BCR signaling pathway. Accordingly, we found decreased levels of phosphorylated signaling nodes downstream of the BCR. Crosslinking-mediated BCR activation antagonized CLL cell death triggered by EC-7072, increased the phosphorylation levels of the abovementioned signaling nodes and upregulated BCL2 expression, suggesting that the mithralog disrupts CLL cell viability by targeting the BCR signaling axis at multiple levels. EC-7072 exerted similar or higher antileukemic activity than that of several available CLL therapies and displayed additive or synergistic interaction with these drugs in killing CLL cells. Overall, our findings provide rationale for future investigation to test whether EC-7072 may be a potential therapeutic option for patients with CLL and other B-cell malignancies.
Highlights
Chronic lymphocytic leukemia (CLL), the most common leukemia in adults in western countries, is characterized by the progressive accumulation of mature-appearing clonal B cells expressing CD5, CD23, and CD19 surface markers in the blood, bone marrow and secondary lymphatic tissues
EC-7072 is a mithralog generated by targeted inactivation of a ketoreductase implicated in the biosynthesis of mithramycin A (MTA) [22] (Supplementary Figure 1A)
In line with previous in vivo studies demonstrating that EC-7072 is well-tolerated in mice compared to MTA [25, 26], we found that the mithralog is substantially less toxic than the parental compound against human healthy cells of different tissue origins
Summary
Chronic lymphocytic leukemia (CLL), the most common leukemia in adults in western countries, is characterized by the progressive accumulation of mature-appearing clonal B cells expressing CD5, CD23, and CD19 surface markers in the blood, bone marrow and secondary lymphatic tissues. While a subset of patients with CLL exhibit an indolent form of the disease, a progression of the malignancy is observed in a fraction of patients, who require therapeutic management [2]. The heterogeneous behavior of CLL is, at least in part, underpinned by the presence of cytogenetic aberrations and the degree of somatic hypermutation in the immunoglobulin heavy-chain variable gene (IGHV), which bear great prognostic and therapeutic value [3]. Patients with unmutated IGHV typically suffer from an aggressive variant of CLL, while mutated IGHV correlates with a more indolent disease. Whole-genome/exome sequencing studies have unveiled heterogeneity within the malignancy [4,5,6] and recent epigenomic analyses uncovered distinct chromatin landscapes associated to clinical subtypes [7], altogether highlighting the complexity of CLL
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