Hematoxylin compounds can specifically kill CALR freak disease cells

Overview

• Post By : Kumar Jeetendra


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


• Date: 20 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). Scientists of the research group 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 now identified hematoxylin as a publication CALR inhibitor. The study, published in the renowned journal Blood, shows how hematoxylin compounds influence a specific domain of CALR and kill those CALR mutant cells which were identified as the cause of disease in MPN patients. The discovery has enormous therapeutic potential and gives hope for new treatment options.

In medicine, a group of malignant disorders of the bone marrow is known as myeloproliferative neoplasms. This special sort of blood cancer is characterized by increased formation of blood cells, vulnerability to thrombosis and frequent transformation to acute leukemia. In the lab of Robert Kralovics it had been discovered 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 lead to myeloid leukemia, has also been scientifically 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 from the research 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 treatment approaches for myeloproliferative neoplasms.

Hematoxylin chemicals kill CALR mutated cells
The scientists used so-called in-silico docking studies for this purpose. “Fundamentally, these are computer-based simulations of biochemical processes – virtual’screenings’ that empower increasingly accurate predictions,” says study author Ruochen Jia. The results demonstrated a group of chemicals as binders for a particular domain of calreticulin, which selectively kill the mutated CALR cells. A hematoxylin compound proved to be particularly efficient. So far, hematoxylin has been used as a dye especially in histological staining processes.

Ray of hope for primary myelofibrosis therapy
“Our analysis 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 particularly benefit from the new therapeutic approach.”