Frequency of molecular mutations in classical MPNs
| Affected pathways . | Mutation . | PMF (%) . | PV (%) . | ET (%) . | Localization/relevance . |
|---|---|---|---|---|---|
| Cytokine signaling | JAK2V617F | 50-60 | 95 | 50-60 | Chromosome 9p24. Most frequent gain-of-function mutation in PV2-5 |
| JAK2 exon 12 | — | 3-4 | — | A gain-of-function mutation, although outside the auto-inhibitory domain of JAK2. Not found in ET/PMF, can be present in post–PV-MF | |
| MPL | 9 | — | 4 | Chromosome 1p34. A gain-of-function mutation6 | |
| CALR | 20-25 | — | 20-25 | Chromosome 19p13.27,8 All described mutations are either indels in the last exon encoding for the C-terminal amino acid of CALR protein (type 1: 52 bp deletion; type 2: 5 bp insertion are the most common), resulting in a mutant protein with loss of ER retention signal | |
| CBL | 6 | — | Rare | Chromosome 11q23.3. A loss-of-function mutation with loss of inhibition of cytokine signaling due to abrogated CBL ubiquitin ligase activity42 | |
| LNK | Rare | Rare | Rare | Chromosome 12p24. A loss-of-function mutation with resultant loss of LNK-associated negative regulation of cytokine receptor signaling44 | |
| Spliceosomes | SRSF2 | 17 | — | — | SRSF2 mutations are relatively common in PMF, cluster with IDH mutations, and are independently predictive of poor outcome50 |
| SF3B1 | 6.5 | — | Rare | A spliceosome mutation. Mutually exclusive of other spliceosomal mutations49 | |
| Epigenetic modifiers | ASXL1 | 8-26 | 2 | Rare | Chromosome 20q11.21. ASXL1 encodes a transcription factor, which functions through histone modification. Mutations affecting exon 12 are found mostly in PMF47,48 |
| IDH1/2 | 4.2 | 1.9 | 0.8 | Chromosomes 2q33.3/15q26.1. Mutants cause overproduction of 2-hydroxyglutarate, which inhibits TET2/other KG-dependent enzymes.43 Presence of mutation may be explored therapeutically, similar to the ongoing IDH inhibitor studies in AML | |
| EZH2 | 13 | 3 | — | Chromosome 7q35. Mutations lead to loss of epigenetic regulation, and are typically associated with poor outcome in PMF46 | |
| TET2 | 8 | 10 | 5 | Chromosome 4q24. Loss-of-function mutations resulting in decreased 5-hydroxymethylcytosine, and interfering with cytosine demethylation.45 TET2 mutation may have an impact on ET vs PV phenotype (see text) |
| Affected pathways . | Mutation . | PMF (%) . | PV (%) . | ET (%) . | Localization/relevance . |
|---|---|---|---|---|---|
| Cytokine signaling | JAK2V617F | 50-60 | 95 | 50-60 | Chromosome 9p24. Most frequent gain-of-function mutation in PV2-5 |
| JAK2 exon 12 | — | 3-4 | — | A gain-of-function mutation, although outside the auto-inhibitory domain of JAK2. Not found in ET/PMF, can be present in post–PV-MF | |
| MPL | 9 | — | 4 | Chromosome 1p34. A gain-of-function mutation6 | |
| CALR | 20-25 | — | 20-25 | Chromosome 19p13.27,8 All described mutations are either indels in the last exon encoding for the C-terminal amino acid of CALR protein (type 1: 52 bp deletion; type 2: 5 bp insertion are the most common), resulting in a mutant protein with loss of ER retention signal | |
| CBL | 6 | — | Rare | Chromosome 11q23.3. A loss-of-function mutation with loss of inhibition of cytokine signaling due to abrogated CBL ubiquitin ligase activity42 | |
| LNK | Rare | Rare | Rare | Chromosome 12p24. A loss-of-function mutation with resultant loss of LNK-associated negative regulation of cytokine receptor signaling44 | |
| Spliceosomes | SRSF2 | 17 | — | — | SRSF2 mutations are relatively common in PMF, cluster with IDH mutations, and are independently predictive of poor outcome50 |
| SF3B1 | 6.5 | — | Rare | A spliceosome mutation. Mutually exclusive of other spliceosomal mutations49 | |
| Epigenetic modifiers | ASXL1 | 8-26 | 2 | Rare | Chromosome 20q11.21. ASXL1 encodes a transcription factor, which functions through histone modification. Mutations affecting exon 12 are found mostly in PMF47,48 |
| IDH1/2 | 4.2 | 1.9 | 0.8 | Chromosomes 2q33.3/15q26.1. Mutants cause overproduction of 2-hydroxyglutarate, which inhibits TET2/other KG-dependent enzymes.43 Presence of mutation may be explored therapeutically, similar to the ongoing IDH inhibitor studies in AML | |
| EZH2 | 13 | 3 | — | Chromosome 7q35. Mutations lead to loss of epigenetic regulation, and are typically associated with poor outcome in PMF46 | |
| TET2 | 8 | 10 | 5 | Chromosome 4q24. Loss-of-function mutations resulting in decreased 5-hydroxymethylcytosine, and interfering with cytosine demethylation.45 TET2 mutation may have an impact on ET vs PV phenotype (see text) |
IDH, isocitrate dehydrogenase; Indels, insertions and deletions; KG, ketoglutarate.