The study shows that hematoxylin can selectively kill cancers with a mutated form of the calreticulin gene (CALR), common in a group of bone marrow cancers called myeloproliferative neoplasms (MPN).
Researchers have identified a novel inhibitor that was able to selectively kill bone marrow cancer cells in mouse models. The team said their discovery has enormous therapeutic potential for patients with myeloproliferative neoplasia (MPN), a group of malignant diseases of the bone marrow, and gives hope for new treatment options.
Patients with MPN often have a mutated carcinogenic form of the calreticulin gene (CALR). In a new study, researchers led by Robert Kralovics, Associate Principal Investigator at the Austrian Academy of Sciences CeMM Research Center for Molecular Medicine and group leader at the Medical University of Vienna, identified that hematoxylin acts as an inhibitor of CALR and demonstrated that hematoxylin compounds can selectively kill CALR mutant cells that are believed to cause MPN.
MPNs are a special type of blood cancer, characterized by increased blood cell formation, vulnerability to thrombosis, and frequent transformation to acute leukemia. In 2013, Kralovics’ laboratory discovered that carcinogenic calreticulin gene (CALR) mutations were frequently found in affected patients, these are now used clinically as diagnostic and prognostic markers.
Mutated CALR functions as an oncogene, with its carcinogenic effects arising from interactions between the N-glucan-binding domain (GBD) of CALR and the thrombopoietin receptor. One of the researchers in Kralovics’ group, Ruochen Jia, was looking for a way to stop this interaction and prevent one of the growth advantages of mutated CALR cells. They used in silico Coupling studies for this purpose: “Basically, these are computer-based simulations of biochemical processes – virtual ‘scans’ that allow increasingly precise predictions,” Jia said.
The researchers said that by doing this, it became clear that a group of chemicals called catechins, and most notably hematoxylin, could inhibit the growth of cells with the CALR oncogene and selectively kill them by inducing apoptosis. Therefore, the team concluded that hematoxylin may be a promising therapy for MPN.
“Our data suggest that small molecules that target the N-glycan binding domain of CALR can selectively kill cells mutated in CALR by disrupting the interaction between CALR and the thrombopoietin receptor and inhibiting oncogenic signaling,” he said. Jia.
“Our study demonstrates the enormous therapeutic potential of CALR inhibitor therapy,” says Kralovics. “Treatment of patients with primary myelofibrosis (PMF) continues to produce poor clinical outcomes. They have the clearest tendency to develop acute myeloid leukemia. Since about a third of PMF patients have a CALR mutation, they could particularly benefit from the new therapeutic approach. “
The research was published in Blood.