Chasing down the triple-negative myeloproliferative neoplasms: Implications for molecular diagnostics

Abstract

The majority of patients with classical myeloproliferative neoplasms (MPN) of polycythemia vera, essential thrombocythemia, and primary myelofibrosis harbor distinct disease-driving mutations within the JAK2, CALR, or MPL genes. The term triple-negative has been recently applied to those MPN without evidence of these consistent mutations, prompting whole or targeted exome sequencing approaches to determine the driver mutational status of this subgroup. These strategies have identified numerous novel mutations that occur in alternative exons of both JAK2 and MPL, the majority of which result in functional activation. Current molecular diagnostic approaches may possess insufficient coverage to detect these alternative mutations, prompting further consideration of targeted exon sequencing into routine diagnostic practice. How to incorporate these illuminating findings into the expanding molecular diagnostic algorithm for MPN requires continual attention.

Keywords: CALR; JAK2; MPL; molecular diagnostics; myeloproliferative neoplasms.

Figure 1.

Distribution of driver mutations in polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF).

Figure 2.

Novel activating mutations of JAK2 and MPL in triple-negative MPN. Those mutations indicated in red are the most frequently observed in MPN.