Myeloproliferative Neoplasm-like Mutations of Calreticulin Induce Phenotypes Associated with Calreticulin Dysfunction in

In previous research, we created a model with homozygous mutations in calreticulin similar to those found in patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF), two myeloproliferative neoplasms (MPNs). This model, lacking JAK orthologs, enabled us to examine the transcriptomic effects caused by mutant calreticulin without the influence of JAK/STAT activation, the primary pathogenic mechanism associated with calreticulin mutations known to date. Most of the gene expression changes observed seemed to be due to a partial loss of protein function, with the alteration of the extracellular matrix being particularly notable. In this study, our aim was to determine whether this model exhibited any phenotype related to these transcriptomic alterations. The results demonstrate that these strains exhibit multiple phenotypes related to the alteration of the extracellular matrix, fat levels, and fertility, which could be a possible consequence of a partial loss of calreticulin function. These phenotypes resemble some of the clinical and molecular characteristics described in patients with MPNs, but they had never before been linked to a loss of protein function in humans. Thus, these results collectively suggest that mutations could have significant effects on MPNs due to loss of protein function. Delving deeper into these effects to develop innovative therapies for these patients offers considerable potential and interest, given that targeted therapies for these patients have not yielded very promising results so far.