Molecular profiling in MPN: who should have it and why?

Abstract

Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) are a group of blood cancers that result from somatic mutations in hematopoietic stem cells, causing constitutive activation of JAK-STAT signaling pathways with consequent overproduction of 1 or more myeloid lineages. The initiating event in MPN pathogenesis is a genetic mutation, and consequently molecular profiling is central to the diagnosis, risk stratification, and, increasingly, monitoring of therapy response in persons with MPN. In this review we summarize current approaches to molecular profiling of classical MPNs (essential thrombocythemia, polycythemia vera, and myelofibrosis), using illustrative clinical case histories to demonstrate how genetic analysis is already fully integrated into MPN diagnostic classification and prognostic risk stratification. Molecular profiling can also be used in MPN to measure response to therapy both in clinical trials and increasingly in routine clinical practice. Taking a forward look, we discuss how molecular profiling in MPN might be used in the future to select specific molecularly targeted therapies and the role of additional genetic methodologies beyond mutation analysis.

Graphical abstract

Figure 1.

The life history of MPNs. The gain of an MPN-driver mutation in a hematopoietic stem cell (HSPC) progenitor, such as JAK2-p.V617F, may occur as early as during embryogenesis. Over a long period of latency likely measured in decades, clonal hematopoiesis develops. The transition to an MPN ensues in a minority of patients, and subsequent acquisition of deleterious genetic mutations, eg, TP53 during clonal evolution, results in a secondary AML. The ultimate aim of therapy is disease modification, by reducing the clonal burden of disease, ie, using JAK2-p. V617F VAF as a surrogate marker. sAML, secondary acute myeloid leukemia.

Figure 2.

Laboratory techniques used for the diagnostics and prognostication of MPNs and the future. FISH, fluorescence in situ hybridization; PCR, polymerase chain reaction; SNP, single nucleotide polymorphism.

Figure 3.

Timeline of key discoveries in MPNs and single-cell methodologies. Reproduced from O'Sullivan et al with permission. Mk, megakaryocyte; XCIP, X-chromosome inactivation pattern.