Table 3.
Recurrent Additional Mutations in MPN
| Gene | Function/Mutation Types | Frequency (%) | Prognostic Impact on MPN | References | ||||
|---|---|---|---|---|---|---|---|---|
| PV | ET | MF | BP | |||||
| DNA methylation | ||||||||
| TET2 | Demethylation through oxidation of 5-methyl-cytosine (5-mc) into 5-hydroxymetylcytosine (5-hmc), an important process in stem cell gene regulation. Heterozygous and homozygous loss-of-function mutations in catalytic domain are described. | 10–20 | 10–15 | 20 | 25 | No defined impact on survival and thrombosis | [23,54,60,108] | |
| DNMT3A | Principal factor of DNA/histone methylation in blood stem cells. Nonsense/frameshift and missense mutations are described, resulting in reduce methyltransferase activity. | 5 | 5 | 5–15 | 20 | Detrimental effect in MF and inferior overall survival. | [54,60,108] | |
| IDH1/2 | Mutant proteins acquired the ability to convert alpha-ketoglutarate (a-KG) to 2 -hydroxyglutarate (2-HG), favouring leukemogenesis through epigenetic dysregulation of some genes. Mutations are heterozygous and occur mostly as point missense mutations at residues R132 in IDH1 and R140 or R172 in IDH2. | <2 | <2 | 3–5 | 15–25 | Detrimental effect in MF and inferior overall survival | [66,109] | |
| Histone modification | ||||||||
| ASXL1 | DNA methylation and transcription repression. Mutations are heterozygous nonsense/frameshift and occur mostly in exon 12 | 1–10 | 5–10 | 18–35 | 20–40 | Risk of fibrotic and leukemic transformation | [54,61,62,66,85,110,111] | |
| EZH2 | Histone methyltransferase and transcription repression. Heterozygous and homozygous loss-of-function mutations mostly in SET2 domain are described. | 1–3 | 0–3 | 0–9 | 13–15 | Risk of fibrotic and leukemic transformation | [112,113] | |
| mRNA splicing | ||||||||
| SF3B1 | Subunit 1 of the splicing factor 3b protein complex. Heterozygous missense mutations in exons 14–16, hotspot K700E is the most frequent. | 5 | 3 | 10 | 4–7 | Increased risk of fibrotic transformation | [54] | |
| SRSF2 | Necessary for the splicing of pre-mRNA. It is required for formation of the earliest ATP-dependent splicing complex and interacts with spliceosomal components bound to both the 5ʹ- and 3ʹ-splice sites during spliceosome assembly. Heterozygous mutations and small in-frame deletions around hotspot P95 are frequent. | <3 | <3 | 10–20 | 10–20 | Increased risk of leukemic transformation and reduced overall survival in MPN | [61,114–117] | |
| U2AF1 | U2 Auxiliary factor 1, comprising a large and a small subunit, is a non-snRNP (small nuclear ribonucleoprotein) protein required for the binding of U2 snRNP to the pre-mRNA branch site. Heterozygous missense mutations around hotspot S34 and Q157 are described. | 1–2 | 1–2 | 16 | 6 | Associated with disease progression and reduced overall survival in MF | [60,69,118] | |
| ZRSR2 | Protein associates with the U2 auxiliary factor heterodimer, which is required for the recognition of a functional 3ʹ splice site in pre-mRNA splicing. Frameshift/nonsense and missense mutations are described. | 1–2 | 1–2 | 10 | 5 | No defined impact on survival and thrombosis | [60,108] | |
| Signalling | ||||||||
| LNK/SH2B3 | Adaptor protein that inhibits signalling through cytokine and tyrosine kinase receptors, including JAK2. Mostly heterozygous missense mutations are described as somatic or germline, also in the context of familial cases of MPN. | 1–3 | 0–5 | 0–6 | 10 | No defined impact on survival and thrombosis. | [54,60,108,119–121] | |
| CBL | Mutations lead to increased STAT5 phosphorylation, cytokine hypersensitivity and cell proliferation; mostly homozygous missense substitutions. | <1 | 0–2 | 0–6 | 4 | Reduced overall survival in MF, resistance to JAKi | [60,108,122,123] | |
| NRAS/KRAS | Heterozygous missense mutations, particularly in codons 12, 13 and 61 led to a constitutive activation of growth signalling. | <1 | <1 | 3–4 | 7–15 | Reduced overall survival in MF, resistance to JAKi | [60,108,123,124] | |
| PTPN11 | Missense mutations in Src-homology 2 (N-SH2) and phosphotyrosine phosphatase (PTP) domains | <1 | <1 | 1 | 2–5 | Reduced overall survival in BP | [108] | |
| Transcription factors | ||||||||
| RUNX1 | Element of core bonding factor (CBF) heterodimer. Essential role in normal hematopoiesis. Missense, frameshift, and nonsense mutations causing loss-of-function. | <1 | <1 | 3–4 | 4–13 | Reduced overall survival in BP | [46] | |
| NFE2 | Mostly heterozygous frameshift mutations, leading to over-expression of wild-type protein functions. | 2–3 | 1 | 1–5 | 11–35 | No defined impact on survival or thrombosis | [125,126] | |
| PPM1D | Encodes a protein phosphatase that regulates the DNA damage response pathway by inhibiting p53 and other tumor-suppressors through dephosphorylation. | 2 | 1 | 1 | NA | No defined impact on survival or thrombosis | [108,127] | |
| TP53 | Encodes a tumor suppressor protein that responds to different cellular stresses to regulate expression of target genes, inducing cell cycle arrest and apoptosis. Mostly missense mutations. | 1 | 2–3 | 2–3 | 11–35 | Associated with disease progression and reduced overall survival in all MPN | [60,108] | |
Abbreviations: PV, polycythemia vera; ET, essential thrombocythemia; MF, myelofibrosis; BP, blast-phase; MPN, myeloproliferative neoplasms; JAKi, JAK inhibitors.