Somatic mutations in MPN
| Gene function and symbol . | Location . | Type of mutations . | Protein function . | Frequency . | Consequences . | Reference . |
|---|---|---|---|---|---|---|
| Signaling MPN driver | ||||||
| JAK2 | 9p24 | JAK2V617F | Tyrosine kinase associated with cytokine receptors | 95% PV, 50%-60% PMF and ET | Increased RBC, platelet, and granulocyte production | 4,,-7 |
| JAK2 exon 12 | 3% PV | Increased RBC | 17 | |||
| MPL | 1p34 | MPL515L/K/A/R MPLS505N | TPOR | 2%-3% ET | Increased platelet production | 19, 22, 23 |
| Other missense mutations | 3-5% PMF | 25 | ||||
| CALR | 19p13 | Indel exon 9 | Mutant: activator of MPL | 20%-25% ET, 25%-30% PMF | Increased platelet production | 28, 29 |
| Other signaling | ||||||
| LNK | 12q24 | Missense (loss of function) deletion | Negative regulator of JAK2 | 1% ET, 2% PMF | Synergy with JAK2V617F-Disease progression | 35 |
| CBL | 11q23;3 | Missense (loss of function) | Cytokine receptor internalization | 4% PMF | Disease progression (progression to AML) | 110 |
| NRAS | 1p13.2 | Missense (activation) | ERK/MAPK signaling | Rare PMF | Progression to leukemia (5%-10% in secondary AML) | 65 |
| NF1 | 17q11 | Missense deletion | ERK/MAPK signaling | Rare PMF | Progression to leukemia (5%-10% in secondary AML) | 66 |
| FLT3 | 13q12 | FLT3-ITD | Cytokine receptor (FLT3-L) | MPN (<3%) | Progression to leukemia (10%-15% in secondary AML) | 100 |
| DNA methylation | ||||||
| TET2 | 4q24 | Missense, nonsense deletion | α-Ketoglutarate–dependent dioxygenase | 10%-20% MPN (ET, PV, and PMF) | Initiation, | 70 |
| Oxidation of 5mC into 5hmC and active 5mC demethylation | Mutations on 2 alleles associated with progression | |||||
| DNMT3A | 2p23 | Missense, hotspot | DNA methylase, de novo methylation | 5%-10% MPN (ET, PV, and PMF) | Initiation | 74 |
| IDH1 | 2q33.3 | Missense, hotspot | Neomorphic enzyme, generation of 2-hydroxyglutarate blocking α-ketoglutarate–dependent enzymes | 1%-3% PMF | Initiation, Disease progression | 111 |
| IDH2 | 15q26.1 | Missense, hotspot | Neomorphic enzyme, generation of 2-hydroxyglutarate blocking α-ketoglutarate–dependent enzymes | 1%-3% PMF | Initiation, Disease progression | 111 |
| Histone modifications | ||||||
| EZH2 | 7q35-36 | Missense, indel | H3K27 methyltransferase, loss of function | 5%-10% PMF | Initiation | 82, 83 |
| Disease progression | ||||||
| ASXL1 | 20q11 | Nonsense/ indel | Chromatin-binding protein associated with PRC1 and 2 | 25% PMF | Initiation | 69 |
| 1%-3% ET/PV | Rapid progression | |||||
| Transcription factors | ||||||
| TP53 | 17p13.1 | Missense/ indel | Transcription factor regulating cell cycle, DNA repair and apoptosis | <5% (20% of sAML) | Progression to leukemia (mutations on both alleles) complex karyotype | 98 |
| CUX1 | 7q22 | Deletion 7p | Transcription factor regulating TP53 and ATM | <3% | Progression to leukemia | 112 |
| IKZF1 | 7p12.2 | Deletion 7p, indel | Master transcription factor in lymphopoiesis | <3% | Progression to leukemia | 112 |
| ETV6 | 12p13 | Missense/ indel | Transcription factor of the ETs family | <3% | Progression to leukemia | 112 |
| RUNX1 | 21q22.3 | Nonsense/ missense/ indel | Master transcription factor in hematopoiesis | <3% (10% of sAML) | Progression to leukemia | 112 |
| RNA splicing | ||||||
| SRSF2 | 17q25.1 | Missense, hotspot | Serine/arginine-rich pre- RNA splicing factor | <2% ET 10%-15% PMF (association with IDH mutations) | Initiation? Progression | 94 |
| SF3B1 | 2q33.1 | Missense | RNA-splicing factor 3b subunit 1, part of U2 | <3% ET | Phenotypic change (anemia) | 113 |
| U2AF1 | 21q22.3 | Missense | U2 small nuclear RNA-splicing factor | 10%-15% PMF | Phenotypic change (anemia) | 94 |
| Gene function and symbol . | Location . | Type of mutations . | Protein function . | Frequency . | Consequences . | Reference . |
|---|---|---|---|---|---|---|
| Signaling MPN driver | ||||||
| JAK2 | 9p24 | JAK2V617F | Tyrosine kinase associated with cytokine receptors | 95% PV, 50%-60% PMF and ET | Increased RBC, platelet, and granulocyte production | 4,,-7 |
| JAK2 exon 12 | 3% PV | Increased RBC | 17 | |||
| MPL | 1p34 | MPL515L/K/A/R MPLS505N | TPOR | 2%-3% ET | Increased platelet production | 19, 22, 23 |
| Other missense mutations | 3-5% PMF | 25 | ||||
| CALR | 19p13 | Indel exon 9 | Mutant: activator of MPL | 20%-25% ET, 25%-30% PMF | Increased platelet production | 28, 29 |
| Other signaling | ||||||
| LNK | 12q24 | Missense (loss of function) deletion | Negative regulator of JAK2 | 1% ET, 2% PMF | Synergy with JAK2V617F-Disease progression | 35 |
| CBL | 11q23;3 | Missense (loss of function) | Cytokine receptor internalization | 4% PMF | Disease progression (progression to AML) | 110 |
| NRAS | 1p13.2 | Missense (activation) | ERK/MAPK signaling | Rare PMF | Progression to leukemia (5%-10% in secondary AML) | 65 |
| NF1 | 17q11 | Missense deletion | ERK/MAPK signaling | Rare PMF | Progression to leukemia (5%-10% in secondary AML) | 66 |
| FLT3 | 13q12 | FLT3-ITD | Cytokine receptor (FLT3-L) | MPN (<3%) | Progression to leukemia (10%-15% in secondary AML) | 100 |
| DNA methylation | ||||||
| TET2 | 4q24 | Missense, nonsense deletion | α-Ketoglutarate–dependent dioxygenase | 10%-20% MPN (ET, PV, and PMF) | Initiation, | 70 |
| Oxidation of 5mC into 5hmC and active 5mC demethylation | Mutations on 2 alleles associated with progression | |||||
| DNMT3A | 2p23 | Missense, hotspot | DNA methylase, de novo methylation | 5%-10% MPN (ET, PV, and PMF) | Initiation | 74 |
| IDH1 | 2q33.3 | Missense, hotspot | Neomorphic enzyme, generation of 2-hydroxyglutarate blocking α-ketoglutarate–dependent enzymes | 1%-3% PMF | Initiation, Disease progression | 111 |
| IDH2 | 15q26.1 | Missense, hotspot | Neomorphic enzyme, generation of 2-hydroxyglutarate blocking α-ketoglutarate–dependent enzymes | 1%-3% PMF | Initiation, Disease progression | 111 |
| Histone modifications | ||||||
| EZH2 | 7q35-36 | Missense, indel | H3K27 methyltransferase, loss of function | 5%-10% PMF | Initiation | 82, 83 |
| Disease progression | ||||||
| ASXL1 | 20q11 | Nonsense/ indel | Chromatin-binding protein associated with PRC1 and 2 | 25% PMF | Initiation | 69 |
| 1%-3% ET/PV | Rapid progression | |||||
| Transcription factors | ||||||
| TP53 | 17p13.1 | Missense/ indel | Transcription factor regulating cell cycle, DNA repair and apoptosis | <5% (20% of sAML) | Progression to leukemia (mutations on both alleles) complex karyotype | 98 |
| CUX1 | 7q22 | Deletion 7p | Transcription factor regulating TP53 and ATM | <3% | Progression to leukemia | 112 |
| IKZF1 | 7p12.2 | Deletion 7p, indel | Master transcription factor in lymphopoiesis | <3% | Progression to leukemia | 112 |
| ETV6 | 12p13 | Missense/ indel | Transcription factor of the ETs family | <3% | Progression to leukemia | 112 |
| RUNX1 | 21q22.3 | Nonsense/ missense/ indel | Master transcription factor in hematopoiesis | <3% (10% of sAML) | Progression to leukemia | 112 |
| RNA splicing | ||||||
| SRSF2 | 17q25.1 | Missense, hotspot | Serine/arginine-rich pre- RNA splicing factor | <2% ET 10%-15% PMF (association with IDH mutations) | Initiation? Progression | 94 |
| SF3B1 | 2q33.1 | Missense | RNA-splicing factor 3b subunit 1, part of U2 | <3% ET | Phenotypic change (anemia) | 113 |
| U2AF1 | 21q22.3 | Missense | U2 small nuclear RNA-splicing factor | 10%-15% PMF | Phenotypic change (anemia) | 94 |
ATM, ataxia-telangiectasia mutated; RBC, red blood cell; sAML, secondary AML.