Mutant Calreticulin in MPN: Mechanistic Insights and Therapeutic Implications

Abstract

Purpose of review: More than a decade following the discovery of Calreticulin (CALR) mutations as drivers of myeloproliferative neoplasms (MPN), advances in the understanding of CALR-mutant MPN continue to emerge. Here, we summarize recent advances in mehanistic understanding and in targeted therapies for CALR-mutant MPN.

Recent findings: Structural insights revealed that the mutant CALR-MPL complex is a tetramer and the mutant CALR C-terminus is exposed on the cell surface. Targeting mutant CALR utilizing antibodies is the leading therapeutic approach, while mutant CALR-directed vaccines are also in early clinical trials. Additionally, chimeric antigen receptor (CAR) T-cells directed against mutant CALR are under evaluation in preclinical models. Approaches addressing the cellular effects of mutant CALR beyond MPL-JAK-STAT activation, such as targeting the unfolded protein response, proteasome, and N-glycosylation pathways, have been tested in preclinical models. In CALR-mutant MPN, the path from discovery to mechanistic understanding to direct therapeutic targeting has advanced rapidly. The longer-term goal remains clonally-selective therapies that modify the disease course in patients.

Fig. 1

Therapeutic targeting in CALR-mutant MPN. A) The mutant CALR-MPL tetrameric complex on the cell surface, showing the mutant CALR C-terminus is exposed and that mutant CALR interacts with immature N-glycans in the extracellular domain of MPL to constitutively activate the JAK-STAT pathway. B) Treatment with pegylated IFNα generally leads to a significantly reduced variant allele frequency in JAK2V617F + MPN patients but not in CALR-mutant MPN patients. C) Mutant CALR-specific antibodies can bind to the mutant CALR-MPL complex on the cell surface to block MPL-JAK-STAT signaling. Addition of a JAK2 inhibitior (e.g. ruxolitinib) may further inhibit JAK-STAT signaling. D) Bi-specific antibodies can bind both mutant CALR bound to MPL, as well as the CD3 receptor, to bring CALR-mutant MPN cells and T-cells in close proximity to facilitate T-cell killing. E) Combining a mutant CALR-directed vaccine with a checkpoint inhibitor (e.g. ipilimumab), or an adjuvant (e.g. poly-ICLC and keyhole limpet hemocyanin), are therapeutic strategies under evaluation in early phase clinical trials