Recurrent somatic gene mutations in myeloproliferative neoplasms (MPNs) and secondary acute myeloid leukemia (AML)
| Gene . | Function . | Location and type of mutation . | Frequency, % . | Clinical impact . | |||
|---|---|---|---|---|---|---|---|
| PV . | ET . | PMF . | Post-MPN AML . | ||||
| Disease driver mutations | |||||||
| JAK2 | JAK-STAT signaling | V617F or exon 12 | 98% | 55% | 60% | — | WHO/ICC criterion for MPN diagnosis |
| MPL | TPO receptor JAK-STAT signaling | Exon 10 | 0% | 5%-7% | 7%-10% | — | WHO/ICC criterion for MPN diagnosis |
| CALR | Chaperone protein CALR-mut binds and activates MPL | Frameshift in exon 9 | 0% | 25%-30% | 20%-30% | — | WHO/ICC criterion for MPN diagnosis |
| Clonal driver mutations | |||||||
| TET2 | Epigenetic regulation | All exons | 10%-20% | 3%-10% | 10%-20% | 19%-25% | No prognostic impact reported |
| DNMT3A | Epigenetic regulation | R882 and all exons | 5%-10% | 1%-5% | 8%-12% | 3%-17% | No prognostic impact reported |
| IDH1 | Epigenetic regulation | R132 | 1%-2% | 1%-2% | 5%-6% | 13% | HMR in PMF and adverse prognostic impact in all MPN subtypes |
| IDH2 | Epigenetic regulation | R140 or R172 | 1%-2% | 1%-2% | 5%-6% | 7%-15% | HMR in PMF and adverse prognostic impact in all MPN subtypes |
| ASXL1 | Epigenetic regulation | Mostly nonsense / frameshift in the last exon | 2%-7% | 5%-10% | 15%-35% | 17%-47% | HMR in PMF and adverse prognostic impact in all MPN subtypes |
| EZH2 | Epigenetic regulation | All exons | 1%-2% | 1%-2% | 7%-10% | 7%-13% | HMR in PMF and adverse prognostic impact in all MPN subtypes |
| NRAS | ERK/MAPK signaling | G12, G13, or Q61 | <2% | <2% | 2%-4% | 11% | Adverse prognostic impact in all MPN subtypes |
| KRAS | ERK/MAPK signaling | G12, G13, or Q61 | <2% | <2% | 2% | 4%-7% | Adverse prognostic impact in all MPN subtypes |
| SH2B3 | JAK signaling regulation | Exon 2 | 2%-9% | 1%-3% | 2%-4% | 6%-11% | Rare mutations in JAK2-negative MPNs |
| CBL | JAK signaling regulation | Exons 8 and 9 | <2% | <2% | 4% | 4% | Adverse prognostic impact in all MPN subtypes |
| SRSF2 | mRNA splicing | P95 | <2% | <2% | 6%-14% | 7%-22% | HMR in PMF and adverse prognostic impact in all MPN subtypes |
| SF3B1 | mRNA splicing | Exon 14-16 | 2%-3% | 2%-5% | 5%-7% | 7%-11% | Adverse prognostic impact in ET |
| U2AF1 | mRNA splicing | S34 or Q157 | <2% | <2% | 7%-10% | 5%-12% | Adverse prognostic impact in all MPN subtypes |
| NFE2 | Transcriptional factor | All exons | 3%,6% | 1%-7% | 3%-5% | ? | Increased risk of leukemic transformation |
| RUNX1 | Transcriptional factor | All exons | <2% | <2% | 2%-3% | 20% | Adverse prognostic impact in all MPN subtypes |
| TP53 | Transcriptional factor | All exons | <2% | 4%-5% | 16%-50% | Adverse prognostic impact in all MPN subtypes | |
| Gene . | Function . | Location and type of mutation . | Frequency, % . | Clinical impact . | |||
|---|---|---|---|---|---|---|---|
| PV . | ET . | PMF . | Post-MPN AML . | ||||
| Disease driver mutations | |||||||
| JAK2 | JAK-STAT signaling | V617F or exon 12 | 98% | 55% | 60% | — | WHO/ICC criterion for MPN diagnosis |
| MPL | TPO receptor JAK-STAT signaling | Exon 10 | 0% | 5%-7% | 7%-10% | — | WHO/ICC criterion for MPN diagnosis |
| CALR | Chaperone protein CALR-mut binds and activates MPL | Frameshift in exon 9 | 0% | 25%-30% | 20%-30% | — | WHO/ICC criterion for MPN diagnosis |
| Clonal driver mutations | |||||||
| TET2 | Epigenetic regulation | All exons | 10%-20% | 3%-10% | 10%-20% | 19%-25% | No prognostic impact reported |
| DNMT3A | Epigenetic regulation | R882 and all exons | 5%-10% | 1%-5% | 8%-12% | 3%-17% | No prognostic impact reported |
| IDH1 | Epigenetic regulation | R132 | 1%-2% | 1%-2% | 5%-6% | 13% | HMR in PMF and adverse prognostic impact in all MPN subtypes |
| IDH2 | Epigenetic regulation | R140 or R172 | 1%-2% | 1%-2% | 5%-6% | 7%-15% | HMR in PMF and adverse prognostic impact in all MPN subtypes |
| ASXL1 | Epigenetic regulation | Mostly nonsense / frameshift in the last exon | 2%-7% | 5%-10% | 15%-35% | 17%-47% | HMR in PMF and adverse prognostic impact in all MPN subtypes |
| EZH2 | Epigenetic regulation | All exons | 1%-2% | 1%-2% | 7%-10% | 7%-13% | HMR in PMF and adverse prognostic impact in all MPN subtypes |
| NRAS | ERK/MAPK signaling | G12, G13, or Q61 | <2% | <2% | 2%-4% | 11% | Adverse prognostic impact in all MPN subtypes |
| KRAS | ERK/MAPK signaling | G12, G13, or Q61 | <2% | <2% | 2% | 4%-7% | Adverse prognostic impact in all MPN subtypes |
| SH2B3 | JAK signaling regulation | Exon 2 | 2%-9% | 1%-3% | 2%-4% | 6%-11% | Rare mutations in JAK2-negative MPNs |
| CBL | JAK signaling regulation | Exons 8 and 9 | <2% | <2% | 4% | 4% | Adverse prognostic impact in all MPN subtypes |
| SRSF2 | mRNA splicing | P95 | <2% | <2% | 6%-14% | 7%-22% | HMR in PMF and adverse prognostic impact in all MPN subtypes |
| SF3B1 | mRNA splicing | Exon 14-16 | 2%-3% | 2%-5% | 5%-7% | 7%-11% | Adverse prognostic impact in ET |
| U2AF1 | mRNA splicing | S34 or Q157 | <2% | <2% | 7%-10% | 5%-12% | Adverse prognostic impact in all MPN subtypes |
| NFE2 | Transcriptional factor | All exons | 3%,6% | 1%-7% | 3%-5% | ? | Increased risk of leukemic transformation |
| RUNX1 | Transcriptional factor | All exons | <2% | <2% | 2%-3% | 20% | Adverse prognostic impact in all MPN subtypes |
| TP53 | Transcriptional factor | All exons | <2% | 4%-5% | 16%-50% | Adverse prognostic impact in all MPN subtypes | |
Only gene mutations occurring with a frequency of >2% are listed.
CALR-mut, calreticulin mutant; ERK, extracellular signal-regulated kinase; ET, essential thrombocythemia; HMR, high molecular risk category for PMF; ICC, international consensus classification; JAK, Janus kinase; MAPK, mitogen-activated protein kinase; MPL, thrombopoeitin receptor; PMF, primary myelofibrosis; PV, polycythemia vera; TPO, thrombopoietin; WHO, World Health Organization.