Epigenetics in Myeloproliferative Neoplasms

Abstract

A decade on from the description of JAK2 V617F, the MPNs are circumscribed by an increasingly intricate landscape. There is now evidence that they are likely the result of combined genetic dysregulation, with several mutated genes involved in the regulation of epigenetic mechanisms. Epigenetic changes are not due to a change in the DNA sequence but are reversible modifications that dictate the way in which genes may be expressed (or silenced). Among the epigenetic mechanisms, DNA methylation is probably the best described. Currently known MPN‐associated mutations now include JAK2, MPL, LNK, CBL, CALR, TET2, ASXL1, IDH1, IDH2, IKZF1 and EZH2. Enhancing our knowledge about the mutation profile of patients may allow them to be stratified into risk groups which would aid clinical decision making. Ongoing work will answer whether the use of epigenetic therapies as alterative pathway targets in combination with JAK inhibitors may be more effective than single agent treatment.

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

“…All of these epigenetic modifiers act either on DNA or histone/transcription factor methylation. Interestingly, they appear to be the most frequent somatic mutations after JAK2 and CALR in MPN [29]. However, these mutations are not restricted to MPN and are also found in a wide spectrum of other neoplasms, including AML.…”

Analysis of genes encoding epigenetic regulators in myeloproliferative neoplasms: Coexistence of a novel SETBP1 mutation in a patient with a p.V617F JAK2 positive myelofibrosis

“…SETBP1 mutations can coexist with aberrations in other genes frequently mutated in myeloid neoplasms such as CBL, ASXL1, U2AF1 or RUNX1 (3,17,18) thus cooperating in the progression of the disease. However, the coexistence of mutations in SETBP1 and JAK2 in MPNs has not been described to date.…”

“…Furthermore, it is well established that mutations in genes related to epigenetic regulation of gene expression can coexist with mutations in JAK2 and could modulate the progression of the disease (3,19). For instance, TET2 encodes the Tet methylcytosine dioxygenase 2 which catalyzes the conversion of the 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) and plays a key role in active DNA demethylation and it is frequently mutated in patients with MPNs (20).…”

Does SF3B1/TET2 Double Mutation Portend Better or Worse Prognosis Than Isolated SF3B1 or TET2 Mutation?

“…Approximately 20% of patients with MDS have TET2 mutation, and this gene is also frequently mutated in chronic myelomonocytic leukemia and AML (15,25). In addition, TET2 mutations are relatively frequent in patients with myeloproliferative neoplasms, in whom dysplastic features are very infrequently present (26). The clinical significance of TET2 mutations in myeloid neoplasms is still unclear, with most literature reporting no impact (27)(28), some reporting poor prognosis (29)(30)(31)(32)(33), and a few reporting good prognosis (18,34,35).…”