Current WHO classification of Philadelphia-negative myeloproliferative neoplasms, their genetic basis, and clinical relevance of genetic lesions
| Nosologic entities of the WHO classification and founding driver genes and their somatic mutations . | Phenotypic switch and disease progression . | Diagnostic and prognostic implications of genetic lesions . |
|---|---|---|
| Polycythemia vera | ||
| JAK2 (V617F) in about 95% of patients JAK2 exon 12 mutations in about 5% of patients | Patients with polycythemia vera may progress to myelofibrosis, and patients with myelofibrosis evolving from polycythemia vera have a mutant allele burden close to 100%, unambiguously indicating the presence of a dominant clone of cells that are homozygous for the mutation; the occurrence of subclonal driver mutations may lead to leukemic transformation | Polycythemia vera is a condition almost exclusively associated with gain-of-function mutations of JAK2. The combination of erythrocytosis (ie, Hb >17 g/dL in males, and >16 g/dL in females) and JAK2 mutation, in the absence of bone marrow fibrosis, may be considered diagnostic of polycythemia vera |
| Essential thrombocythemia | ||
| JAK2 (V617F) in about 60%-65% of cases MPL exon 10 mutations in about 5% of cases CALR exon 9 indels in about 20%-25% of cases About 5%-10% of patients do not carry any of the above somatic mutations | Transition from heterozygosity to homozygosity for JAK2 (V617F) may be associated with progression from essential thrombocythemia to polycythemia vera; all patients with essential thrombocythemia carrying a somatic mutation in JAK2, MPL, or CARL may progress to secondary myelofibrosis, while the occurrence of subclonal driver mutations may lead to leukemic transformation | The combination of thrombocytosis (>400 × 109/L) and JAK2 (V617F), or an MPL exon 10 mutation, or a CALR exon 9 indel in the absence of bone marrow fibrosis and erythrocytosis may be considered as diagnostic of essential thrombocythemia; patients with a CALR exon 9 mutation have very high platelet counts but a relatively low risk of thrombosis (much lower than that of patients with the JAK2 mutation) |
| Primary myelofibrosis | ||
| JAK2 (V617F) in about 60%-65% of cases MPL exon 10 mutations in about 5% of cases CALR exon 9 indels in about 20%-25% of cases About 5%-10% of patients do not carry any of the above somatic mutations | The occurrence of subclonal driver mutations in genes like ASXL1, DNMT3A, EZH2, IDH1/IDH2, SRSF2, or TP53 is associated with worse clinical course and higher risk of progression to blast phase or leukemic transformation; somatic mutation of ASXL1 appears to have the most detrimental effect | The diagnosis of primary myelofibrosis should now include as a major criterion not only the presence of JAK2 (V617F) or an MPL exon 10 mutation, but also that of a CALR exon 9 indel; patients with myelofibrosis carrying a CALR exon 9 indel have an indolent clinical course, and a far better survival than those carrying JAK2 (V617F) or an MPL mutation, or especially those with nonmutated JAK2, CALR, and MPL; these latter have a very poor prognosis and a particularly high risk of leukemic transformation |
| Nosologic entities of the WHO classification and founding driver genes and their somatic mutations . | Phenotypic switch and disease progression . | Diagnostic and prognostic implications of genetic lesions . |
|---|---|---|
| Polycythemia vera | ||
| JAK2 (V617F) in about 95% of patients JAK2 exon 12 mutations in about 5% of patients | Patients with polycythemia vera may progress to myelofibrosis, and patients with myelofibrosis evolving from polycythemia vera have a mutant allele burden close to 100%, unambiguously indicating the presence of a dominant clone of cells that are homozygous for the mutation; the occurrence of subclonal driver mutations may lead to leukemic transformation | Polycythemia vera is a condition almost exclusively associated with gain-of-function mutations of JAK2. The combination of erythrocytosis (ie, Hb >17 g/dL in males, and >16 g/dL in females) and JAK2 mutation, in the absence of bone marrow fibrosis, may be considered diagnostic of polycythemia vera |
| Essential thrombocythemia | ||
| JAK2 (V617F) in about 60%-65% of cases MPL exon 10 mutations in about 5% of cases CALR exon 9 indels in about 20%-25% of cases About 5%-10% of patients do not carry any of the above somatic mutations | Transition from heterozygosity to homozygosity for JAK2 (V617F) may be associated with progression from essential thrombocythemia to polycythemia vera; all patients with essential thrombocythemia carrying a somatic mutation in JAK2, MPL, or CARL may progress to secondary myelofibrosis, while the occurrence of subclonal driver mutations may lead to leukemic transformation | The combination of thrombocytosis (>400 × 109/L) and JAK2 (V617F), or an MPL exon 10 mutation, or a CALR exon 9 indel in the absence of bone marrow fibrosis and erythrocytosis may be considered as diagnostic of essential thrombocythemia; patients with a CALR exon 9 mutation have very high platelet counts but a relatively low risk of thrombosis (much lower than that of patients with the JAK2 mutation) |
| Primary myelofibrosis | ||
| JAK2 (V617F) in about 60%-65% of cases MPL exon 10 mutations in about 5% of cases CALR exon 9 indels in about 20%-25% of cases About 5%-10% of patients do not carry any of the above somatic mutations | The occurrence of subclonal driver mutations in genes like ASXL1, DNMT3A, EZH2, IDH1/IDH2, SRSF2, or TP53 is associated with worse clinical course and higher risk of progression to blast phase or leukemic transformation; somatic mutation of ASXL1 appears to have the most detrimental effect | The diagnosis of primary myelofibrosis should now include as a major criterion not only the presence of JAK2 (V617F) or an MPL exon 10 mutation, but also that of a CALR exon 9 indel; patients with myelofibrosis carrying a CALR exon 9 indel have an indolent clinical course, and a far better survival than those carrying JAK2 (V617F) or an MPL mutation, or especially those with nonmutated JAK2, CALR, and MPL; these latter have a very poor prognosis and a particularly high risk of leukemic transformation |