An overview on CALR and CSF3R mutations and a proposal for revision of WHO diagnostic criteria for myeloproliferative neoplasms.

Disease-specific mutations facilitate diagnostic precision and drug target discovery. In myeloproliferative neoplasms (MPN), this is best exemplified by the chronic myeloid leukemia-associated BCR-ABL1. No other mutation in MPN has thus far shown a similar degree of diagnostic accuracy or therapeutic relevance. However, JAK2 and KIT mutations are detected in more than 90% of patients with polycythemia vera and systemic mastocytosis, respectively, and are therefore used as highly sensitive clonal markers in these diseases. JAK2 and MPL mutations also occur in essential thrombocythemia (ET) and primary myelofibrosis (PMF), but their diagnostic value is limited by suboptimal sensitivity and specificity. The molecular diagnostic gap in JAK2/MPL-unmutated ET/PMF is now partially addressed by the recent discovery of calreticulin (CALR) mutations in the majority of such cases. However, bone marrow morphology remains the central diagnostic platform and is essential for distinguishing ET from prefibrotic PMF and diagnosing patients those do not express JAK2, MPL or CALR (triple-negative). The year 2013 was also marked by the description of CSF3R mutations in the majority of patients with chronic neutrophilic leukemia (CNL). Herein, we argue for the inclusion of CALR and CSF3R mutations in the World Health Organization classification system for ET/PMF and CNL, respectively.