Clinical significance of somatic mutations in classical MPNs
| Gene . | Clinical significance . |
|---|---|
| MPN-driver genes(through gain-of-function mutations, these genes activate the cytokine receptor/JAK2 pathway and their downstream effectors) | |
| JAK2 | Somatic mutation represents a major diagnostic criterion for PV, ET, and PMF |
| CALR | Somatic mutation represents a major diagnostic criterion for ET and PMF |
| MPL | Somatic mutation represents a major diagnostic criterion for ET and PMF |
| Non-MPN-driver, myeloid genes(through loss-of-function mutations, whose occurrence may chronologically precede or follow the acquisition of driver mutations, these genes contribute to phenotypic variability, phenotypic shifts, and progression to more aggressive myeloid neoplasms) | |
| DNMT3A, TET2 | Somatic mutations in these genes are typically associated with age-related clonal hematopoiesis. In MPN, these mutations may variably impact on clinical phenotype and predispose to disease progression. In patients undergoing treatments that target the myeloproliferative clone, these mutations may prevent its eradication and should therefore be monitored to assess the nature and degree of response, at least in clinical trials |
| ASXL1 | Somatic mutations are found in age-related clonal hematopoiesis. In PMF, somatic ASXL1 mutation represents an established unfavorable prognostic factor that may be associated with leukemic transformation |
| EZH2 and other PRC2 members (SUZ12, JARID2, and EED) | EZH2 deletion/inactivation has been shown to cause myelofibrosis in murine models of MPN, suggesting that EZH2 mutation may represent a mechanism of myelofibrotic transformation in ET and PV. Somatic mutation represents an unfavorable prognostic factor in PMF |
| SF3B1, SRSF2, and U2AF1 (spliceosome genes) | Somatic mutation may represent a pathogenetic mechanism of anemia or more generally of cytopenia: in particular, somatic mutations of SF3B1 account for the presence of ring sideroblasts in MPN patients. SRSF2 mutation may be responsible for myelofibrotic transformation through downregulation of EZH2, and represents an unfavorable prognostic factor in PMF. U2AF1 mutation may be associated with leukemic transformation |
| TP53 | Somatic mutation often represents a mechanism of leukemic transformation, typically through transition from heterozygosity to homozygosity for the mutation |
| CBL, CUX1, IDH1/2, IKZF1, and RUNX1 | Somatic mutation (including deletion) may represent a late event associated with leukemic transformation |
| Other cooperating genes | |
| LNK | Germ line or somatic mutation may cooperate with JAK2 (V617F) or CALR mutation to give rise to an MPN phenotype |
| BCR-ABL1 | Comutation with CALR mutation gives rise to a hybrid CML/MPN phenotype |
| Gene . | Clinical significance . |
|---|---|
| MPN-driver genes(through gain-of-function mutations, these genes activate the cytokine receptor/JAK2 pathway and their downstream effectors) | |
| JAK2 | Somatic mutation represents a major diagnostic criterion for PV, ET, and PMF |
| CALR | Somatic mutation represents a major diagnostic criterion for ET and PMF |
| MPL | Somatic mutation represents a major diagnostic criterion for ET and PMF |
| Non-MPN-driver, myeloid genes(through loss-of-function mutations, whose occurrence may chronologically precede or follow the acquisition of driver mutations, these genes contribute to phenotypic variability, phenotypic shifts, and progression to more aggressive myeloid neoplasms) | |
| DNMT3A, TET2 | Somatic mutations in these genes are typically associated with age-related clonal hematopoiesis. In MPN, these mutations may variably impact on clinical phenotype and predispose to disease progression. In patients undergoing treatments that target the myeloproliferative clone, these mutations may prevent its eradication and should therefore be monitored to assess the nature and degree of response, at least in clinical trials |
| ASXL1 | Somatic mutations are found in age-related clonal hematopoiesis. In PMF, somatic ASXL1 mutation represents an established unfavorable prognostic factor that may be associated with leukemic transformation |
| EZH2 and other PRC2 members (SUZ12, JARID2, and EED) | EZH2 deletion/inactivation has been shown to cause myelofibrosis in murine models of MPN, suggesting that EZH2 mutation may represent a mechanism of myelofibrotic transformation in ET and PV. Somatic mutation represents an unfavorable prognostic factor in PMF |
| SF3B1, SRSF2, and U2AF1 (spliceosome genes) | Somatic mutation may represent a pathogenetic mechanism of anemia or more generally of cytopenia: in particular, somatic mutations of SF3B1 account for the presence of ring sideroblasts in MPN patients. SRSF2 mutation may be responsible for myelofibrotic transformation through downregulation of EZH2, and represents an unfavorable prognostic factor in PMF. U2AF1 mutation may be associated with leukemic transformation |
| TP53 | Somatic mutation often represents a mechanism of leukemic transformation, typically through transition from heterozygosity to homozygosity for the mutation |
| CBL, CUX1, IDH1/2, IKZF1, and RUNX1 | Somatic mutation (including deletion) may represent a late event associated with leukemic transformation |
| Other cooperating genes | |
| LNK | Germ line or somatic mutation may cooperate with JAK2 (V617F) or CALR mutation to give rise to an MPN phenotype |
| BCR-ABL1 | Comutation with CALR mutation gives rise to a hybrid CML/MPN phenotype |
The information is from Vainchenker and Kralovics.12