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Targeting the B-Cell Receptor With Mithramycin Analogs in CLL

By: Lauren Harrison, MS
Posted: Monday, February 3, 2020

The mithramycin analog EC-7072 may be a potential therapeutic option for patients with chronic lymphocytic leukemia (CLL) and other B-cell malignancies, as researchers believe it targets components of the B-cell receptor–dependent signaling pathway. Alejandro López-Soto, PhD, of the Universidad de Oviedo, Spain, and colleagues published these results in Frontiers in Immunology.

“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,” the investigators commented.

The researchers utilized blood samples from 63 patients with CLL who were previously untreated. They then performed antibody testing to determine immune cell populations as well as apoptosis studies. RNA-sequencing studies were also performed on the samples.

EC-7072 was found to display high ex vivo cytotoxic activity against the leukemia cell samples. This activity was independent of high-risk prognostic markers and IgHV mutations. This compound was significantly less toxic against T cells and natural killer cells and did not have an effect on the production of interferon-gamma or perforin. It was found to directly trigger caspase-3 dependent apoptosis, which was not affected by microenvironmental factors that the investigators noted are known to sustain leukemia cell survival. EC-7072 drove reprogramming of the transcriptome of leukemia cells, according to RNA-sequencing data, as there was downregulation of multiple components and targets of the B-cell receptor pathway.

In addition, researchers saw decreased levels of phosphorylated signaling nodes downstream of the B-cell receptor. They suggest that EC-7072 disrupts the viability of leukemia cells by targeting the B-cell receptor signaling axis at various levels. This antileukemic activity of EC-7072 appeared to be similar to that of other available CLL therapies and worked in synergy with these drugs.

Disclosure: For full author disclosures, visit frontiersin.org.



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