<p>Impact of Mutational Profile on the Management of Myeloproliferative Neoplasms: A Short Review of the Emerging Data</p>

Abstract

Philadelphia-chromosome negative myeloproliferative neoplasms (MPN) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by an increased risk of thrombosis and progression to acute myeloid leukemia. MPN are associated with driver mutations in JAK2, CALR and MPL which are crucial for the diagnosis and lead to a constitutive activation of the JAK-STAT signaling, independent of cytokine regulation. Moreover, most patients have concomitant mutations in genes involved in DNA methylation, chromatin modification, messenger RNA splicing, transcription regulation and signal transduction. These additional mutations may arise before, in the context of clonal hematopoiesis of indeterminate potential (CHIP), or after the acquisition of the driver mutation. The clinical phenotype of MPN results from complex interactions between mutations and host factors. The increased application of next-generation sequencing (NGS) techniques to a large series of patients with MPN has expanded the knowledge of mutational landscape and contributed to define the clinical significance of mutations. This molecular information is being increasingly used to refine diagnosis, risk stratification, monitoring of residual disease and response to treatment. ASXL1, SRSF2, EZH2, IDH1/IDH2 and U2AF1 mutations are associated with a more advanced disease and reduced overall survival in primary myelofibrosis (PMF), whereas spliceosome mutations in Polycythemia vera (PV) and essential thrombocythemia (ET) adversely affect both overall (SF3B1, SRSF2 in ET and SRSF2 in PV) and myelofibrosis-free (U2AF1, SF3B1 in ET) survival. This review discusses current knowledge of the molecular landscape of MPN, and how the availability of those molecular information may impact patient management.

Synoptic Diagnostics of Myeloproliferative Neoplasms: Morphology and Molecular Genetics

“…In recent years, additional mutations to the driver mutation were detected, especially classic CHIP mutations. In PV, these include TET2 (10–20%), ASXL1 (up to 10%), DNMT3A (5%), and SF3B1 (5%), which affect DNA methylation, histone modification and mRNA splicing ( Table 1 ) [ 34 , 35 , 36 ]. An interesting feature is the time point of acquisition of these secondary mutations and their correlation with the clinical phenotype.…”

“…These secondary mutations, more typically found in CHIP and MDS, are more common in PMF than ET and PV, and might, in part, explain the worse prognosis of PMF. A small number of cases, up to 12% of PMF are so-called triple negative cases lacking the classic driver mutations [ 34 , 41 ]. Deep sequencing identified mutations outside the classic regions of MPL exon 10 in about 10% of these triple-negative cases [ 103 ].…”

“…The mutational landscape of ET is similar to PMF with regard to driver mutations: about 50–60% of cases harbor the JAK2 mutation V617F, but no JAK2 exon 12 mutations, up to 30% show CALR and 3–8% MPL mutations; up to 15% are “triple-negative” for the classic MPN driver mutations and are difficult to separate from reactive thrombocytosis ( Table 1 ) [ 29 , 34 , 38 , 43 , 44 ]. As mentioned above, cases which acquire TET2 or DNMT3A mutations before the JAK2 mutation more often have an ET phenotype [ 35 , 88 ], and the two different types of CALR mutations are more balanced in ET vs. PMF [ 93 ].…”

Lenalidomide: A double‐edged sword for concomitant multiple myeloma and post‐essential thrombocythemia myelofibrosis

“…Two CALR mutations account for approximately 80% of all the subtypes; type‐1 is a 52‐bp deletion (c.1092_1143del p. L367fs*46) and type‐2 is a 5‐bp insertion (c.1154_1155insTTGTC p. K385fs*47), resulting in mutant proteins that lost the ER‐retention motif (KDEL) at the C‐terminus. All other mutations are grouped as type 1‐like and type 2‐like in relation to their corresponding structural similarities and effect on C‐terminal 14 . Based on the International Working Group‐Myeloproliferative Neoplasms Research and Treatment (IWG‐MRT) expert consensus (Table 1), a diagnosis of post‐ET MF was performed by considering the BM histology, development of anemia and increased LDH level 11 …”

“…mutations are grouped as type 1-like and type 2-like in relation to their corresponding structural similarities and effect on C-terminal. 14 Based on the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) expert consensus (Table 1), a diagnosis of post-ET MF was performed by considering the BM histology, development of anemia and increased LDH level. 11 We used the MYSEC-prognostic model, which includes advanced age, hemoglobin level below 11 g/dL, platelet count below 150 × 10 9 /L, circulating blast cells equal to or greater than 3%, CALR-unmutated genotype and the presence of constitutional symptoms as core risk factors, to risk-stratify the patient.…”