Mutations in JAK2 and MPL genes described in myeloproliferative neoplasm (MPN) and MPN-like diseases
| Mutation . | Protein domain . | Somatic or germline . | Disease phenotype . | Found alone or together with another mutation . | Mean allele frequency . | Functional effect (gain-of-function) . |
|---|---|---|---|---|---|---|
| JAK2 mutations (ENST00000381652 transcript) | ||||||
| p.T108A | FERM | germ | PV | JAK2 p.V617F | 0.0007% | Weak |
| p.Y317H | FERM | NT | PMF | CALR | 0.002% | Weak |
| p.H345L | FERM | som | PMF | CALR | 0% | Weak |
| Exon 12 mutations between M535 to F547 | JH2 | som | PV | Alone | 0% | Strong driver gene mutations |
| p.F556V | JH2 | germ | ET | Alone | 0.001% | Weak |
| p.R564Q | JH2 | germ | HT | Alone | 0.003% | Intermediate |
| p.L583_A586delins | JH2 | som | PV | Alone | 0% | Intermediate |
| p.H608N | JH2 | germ | HT | Alone | 0% | Weak |
| p.L611S | JH2 | germ or NT | HT or PV | Alone or with JAK2 p.V617F | 0% | Weak |
| p.V617F | JH2 | som | PV, ET or PMF | Alone | 0.034% | Strong driver gene mutation |
| p.V617I | JH2 | germ or som | HT or ET | Alone | 0% | Weak |
| p.V625F | JH2 | germ | ET, PMF | Alone | 0% | Weak |
| p.E846D | JH1 | germ | HE | Alone | 0.045% | Need cooperating mutation |
| p.R867Q | JH1 | germ | HT | Alone | 0.0005% | Intermediate |
| p.T875N | JH1 | germ or som | HT or PMF | Alone | 0% | Strong |
| p.R755S/R938Q | JH2/1 | germ | HT | Alone | 0.003% | Intermediate |
| p.R1063H | JH1 | germ | HT | Alone | 0.47% | Need cooperating mutation |
| MPL mutations (ENST00000372470 transcript) | ||||||
| p.K39N | EC | germ | HT | Alone or with other MPL mutations | 0.46% and 4.6% in Africans | Reduced cell surface MPL |
| p.P106L | EC | germ | HT for hom | Alone | 0.038% | Reduced cell surface MPL |
| p.T119I | EC | som | ET or PMF | Alone | 0% | Minimal |
| p.S204P/F | EC | som | ET or PMF | Alone | 0% | Weak |
| p.E230G | EC | som | ET or PMF | Alone | 0% | Minimal |
| p.V285E | EC | germ | HT | Alone | 0% | Minimal |
| p.R321W | EC | germ | HT | Alone | 0% | Minimal |
| p.L498W | TM | som | ET | MPL p.S505N | 0% | Intermediate |
| p.L498_H499insVIAL | TM | som | ET | Alone | 0% | Intermediate |
| p.V501A | TM | som or NT | ET or PMF | MPL p.W515L/K or p.S505N | 0% | Intermediate |
| p.S505N | TM | som or germ | HT and ET, PMF | Alone | 0% | Strong driver gene mutation |
| p.W515K/L/A/R | TM | som | ET or PMF | Alone | 0% | Strong driver gene mutation |
| p.Y591D/N | IC | som | ET or PMF | Alone | 0% | Weak |
| Mutation . | Protein domain . | Somatic or germline . | Disease phenotype . | Found alone or together with another mutation . | Mean allele frequency . | Functional effect (gain-of-function) . |
|---|---|---|---|---|---|---|
| JAK2 mutations (ENST00000381652 transcript) | ||||||
| p.T108A | FERM | germ | PV | JAK2 p.V617F | 0.0007% | Weak |
| p.Y317H | FERM | NT | PMF | CALR | 0.002% | Weak |
| p.H345L | FERM | som | PMF | CALR | 0% | Weak |
| Exon 12 mutations between M535 to F547 | JH2 | som | PV | Alone | 0% | Strong driver gene mutations |
| p.F556V | JH2 | germ | ET | Alone | 0.001% | Weak |
| p.R564Q | JH2 | germ | HT | Alone | 0.003% | Intermediate |
| p.L583_A586delins | JH2 | som | PV | Alone | 0% | Intermediate |
| p.H608N | JH2 | germ | HT | Alone | 0% | Weak |
| p.L611S | JH2 | germ or NT | HT or PV | Alone or with JAK2 p.V617F | 0% | Weak |
| p.V617F | JH2 | som | PV, ET or PMF | Alone | 0.034% | Strong driver gene mutation |
| p.V617I | JH2 | germ or som | HT or ET | Alone | 0% | Weak |
| p.V625F | JH2 | germ | ET, PMF | Alone | 0% | Weak |
| p.E846D | JH1 | germ | HE | Alone | 0.045% | Need cooperating mutation |
| p.R867Q | JH1 | germ | HT | Alone | 0.0005% | Intermediate |
| p.T875N | JH1 | germ or som | HT or PMF | Alone | 0% | Strong |
| p.R755S/R938Q | JH2/1 | germ | HT | Alone | 0.003% | Intermediate |
| p.R1063H | JH1 | germ | HT | Alone | 0.47% | Need cooperating mutation |
| MPL mutations (ENST00000372470 transcript) | ||||||
| p.K39N | EC | germ | HT | Alone or with other MPL mutations | 0.46% and 4.6% in Africans | Reduced cell surface MPL |
| p.P106L | EC | germ | HT for hom | Alone | 0.038% | Reduced cell surface MPL |
| p.T119I | EC | som | ET or PMF | Alone | 0% | Minimal |
| p.S204P/F | EC | som | ET or PMF | Alone | 0% | Weak |
| p.E230G | EC | som | ET or PMF | Alone | 0% | Minimal |
| p.V285E | EC | germ | HT | Alone | 0% | Minimal |
| p.R321W | EC | germ | HT | Alone | 0% | Minimal |
| p.L498W | TM | som | ET | MPL p.S505N | 0% | Intermediate |
| p.L498_H499insVIAL | TM | som | ET | Alone | 0% | Intermediate |
| p.V501A | TM | som or NT | ET or PMF | MPL p.W515L/K or p.S505N | 0% | Intermediate |
| p.S505N | TM | som or germ | HT and ET, PMF | Alone | 0% | Strong driver gene mutation |
| p.W515K/L/A/R | TM | som | ET or PMF | Alone | 0% | Strong driver gene mutation |
| p.Y591D/N | IC | som | ET or PMF | Alone | 0% | Weak |
Mutations of JAK2 and MPL genes in MPN and MPN-like diseases were screened in PubMed publications and the Catalogue Of Somatic Mutations In Cancer (COSMIC) database. Only mutations with a functional impact on Janus kinase–signal transducer and activator of transcription (JAK-STAT) signaling and/or cell proliferation were retained. Functional effect was classified as being minimal to strong, as follows: minimal if only a constitutive STAT signaling was found; weak if a hypersensitivity to cytokine was found in transfected cell lines; intermediate if the mutation induced cytokine-independent growth; and strong if a mouse model had an MPN-like phenotype. MPL mutations inducing a reduction of the cell surface expression of thrombopoeitin receptor MPL lead to an increased level of plasmatic thrombopoietin (TPO) that stimulates megakaryopoiesis. The allele frequencies in the general population were extracted from the gnomAD v2.1 database. EC, extracellular; ET, essential thrombocythemia; FERM, protein 4.1R/ezrin/radixin/moesin; germ, germline; HE, hereditary erythropoiesis; hom, homozygous; HT, hereditary thrombocytosis; IC, intracellular; NT, not tested; PMF, primary myelofibrosis; PV, polycythemia vera; som, somatic; TM, transmembrane.