Hematoxylin compounds can specifically kill CALR mutant cancer cells

Overview

• Post By : Kumar Jeetendra


• Source: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences


• Date: 11 Dec,2020

Patients with myeloproliferative neoplasm (MPN), a group of malignant diseases of the bone marrow, often have a carcinogenic mutated form of the calreticulin gene (CALR). Researchers of the research team of Robert Kralovics, Adjunct Principal Investigator in the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences and team leader at the Medical University of Vienna, have identified hematoxylin as a novel CALR inhibitor. The analysis, published in the renowned journal Blood, shows how hematoxylin compounds affect a specific domain of CALR and kill those CALR mutant cells that have been identified as the cause of disease in MPN patients. The discovery has enormous therapeutic potential and gives hope for new treatment options.

In the laboratory of Robert Kralovics it had been found as early as 2013 that carcinogenic mutations of this gene calreticulin (CALR) were frequently found in affected patients and are currently used clinically as diagnostic and prognostic markers.

The mechanism by which the mutated CALR acts as an oncogene, which may cause myeloid leukemia, has also been clinically identified since then. The carcinogenic effect of CALR mutations is based on the interaction of the N-glycan binding domain (GBD) of CALR with the thrombopoietin receptor. Ruochen Jia in the study group of Robert Kralovics in CeMM was searching for a way to prevent this interaction and prevent one of the growth advantages of CALR mutated cells. It became evident that a group of chemicals, most notably hematoxylin, can selectively kill mutated CALR cells. The results thus provide extremely valuable information for possible therapy strategies for myeloproliferative neoplasms.

Hematoxylin compounds kill CALR mutated cells

In our study we tried to identify small molecules that might block the interaction between the mutated CALR and the receptor.”

Robert Kralovics, Adjunct Principal Investigator, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Medical University of Vienna

The scientists used so-called in-silico docking research for this purpose. “Basically, these are computer-based simulations of biochemical processes – virtual’screenings’ that enable increasingly accurate predictions,” says study author Ruochen Jia. The results demonstrated a group of compounds as binders for a specific domain of calreticulin, which kill the mutated CALR cells. A hematoxylin compound was shown to be especially efficient. Up to now, hematoxylin was used as a dye particularly in histological staining processes.

“Our study demonstrates the enormous therapeutic potential of CALR inhibitor therapy,” states Kralovics. “The treatment of patients with primary myelofibrosis (PMF) continues to create poor clinical outcomes. Since about one third of PMF patients have a CALR mutation, they could especially benefit from the new therapeutic approach.”