Molecular Mechanism of Mutant CALR-Mediated Transformation

Abstract

Elf and colleagues used an elegant series of functional and biochemical assays to investigate the molecular mechanism of mutant calreticulin (CALR)-driven cellular transformation in myeloproliferative neoplasms (MPN). Mutant CALR is sufficient to induce MPN in mouse transplantation experiments, and transformation is dependent upon physical interaction mediated by the positive electrostatic charge of the mutant CALR C-terminal domain and the thrombopoietin receptor MPL.

Figure 1. Schematics of the mechanism of mutant CALR-mediated oncogenic transformation

(1) Frameshift mutations (here: p.L367fs*46) in exon 9 of the calreticulin (CALR) gene codes for mutant CALR (CALR^MUT) with a positively charged C-terminal domain instead of the negatively charged C-terminus of wild-type CALR (CALR^WT) protein. (2) CALR^MUT also lacks the C-terminal endoplasmic reticulum (ER) retention signal (KDEL) present in CALR^WT protein. (3) The positive charge of the CALR^MUT C-terminus is required for direct binding to the thrombopoietin receptor (MPL). (4),(5) Binding of CALR^MUT to MPL is required for downstream JAK-STAT activation and oncogenic transformation. Illustration by Barbara Walter.