In 2013, frameshift mutations in exon 9 of the calreticulin (CALR) gene, encoding for an endoplasmic reticulum chaperone protein that interacts with MPL, were found in the majority ofJAK2V617F andMPL mutation-negative ET and PMF patients, thereby completing the “missing piece in the puzzle” of MPN driver mutations13,14. This evidence concerns the gene CALR and essential thrombocythemia.