LAUSR

To the Editor: Myeloproliferative neoplasms (MPN) constitute one of the major categories of myeloid neoplasms, according to the World Health Organization (WHO) classification system. Included under the 2016 WHO MPN category are polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). These three clinicopathologic entities are distinguished from other MPNs, not only by their morphologic features, but also by their close association with the driver mutations JAK2 (Janus kinase 2; 9p24), CALR (calreticulin; 19p13.2), and MPL (myeloproliferative leukemia virus oncogene; 1p34). Mutational frequencies are approximately 97%, 55%, and 65% for JAK2; 0%, 25%, and 20% for CALR; and 0%, 3%, and 8% for MPL, in PV, ET, and PMF, respectively. The discovery of CALR mutations in JAK2/MPL mutation-negative ET and PMF, in 2013, was accompanied by the realization of their distinct phenotypic and prognostic attributes. More than 80% of CALR mutations seen in MPN are classified as either “type 1” or “type 2”; type 1 denotes a 52-bp deletion (p.L367fs*46) and type 2 a 5-bp TTGTC insertion (p.K385fs*47). In one study of 368 CALR-mutated patients with MPN, 206 (56%) harbored type 1, 119 (32%) type 2, and 43 (12%) other CALR variants; the corresponding incidences in PMF were 70%, 13%, and 17% and in ET 51%, 39%, and 10%. In 2014, we reported a higher platelet count in ET patients with type 2 CALR mutations, compared to those with the type 1 variant. The same year, we discovered that the survival advantage of CALR mutations in PMF was restricted to patients with the type 1 variant. Having established the remarkable prognostic distinction between type 1 and type 2 CALR mutations in PMF, and in view of the multiple functions of native CALR, which includes handling of protein folding and transport, we considered the possibility that differences in