Abstract
JAK2, CALR and MPL driver mutations activate JAK/STAT signalling in BCR-ABL1 translocation negative classic myeloproliferative neoplasms (MPN). Detection of these mutations in patients is included in major criteria for establishing diagnoses of polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF).1,2 JAK2 Val617Phe and exon 12 mutations are detected in approximately 98% of PV, while JAK2 Val617Phe, CALR exon 9 frameshift mutations and MPL exon 10 mutations collectively are detectable in 83% of ET and 92% of PMF.2 Mutations in these genes are typically mutually exclusive, however, JAK2 Val617Phe/JAK2 exon 12,3,4 JAK2/CALR,5,6 JAK2/MPL4,6,7 and very rarely CALR/MPL8 comutations have been reported. Further, the presence of multiple independent JAK2 Val617Phe mutations has been demonstrated in the majority of ET patients in one case series, and is one of several lines of evidence that suggest a predisposition in some patients to the development of JAK2 (and other MPN driver) mutations, the nature of which has not been elucidated but may include, genetic predisposition, a preceding clonal mutation or a permissive microenvironment.9 Herein we describe two unusual cases of patients with an MPN, each harboring two driver mutations (JAK2/CALR and JAK2/MPL) and the use of single cell DNA sequencing analysis to further investigate the clonal architecture of these neoplasms. In both cases we demonstrate that the driver mutations represent independent clones and give insight into the potential clonal complexity of this rare phenomenon.
