Table 2.
Mutations in MPNs and their clinical implications.
| Gene | Frequency in MPN [12] | Reported Oncogenic/Likely Oncogenic Mutations and (Reference Transcripts) [3] |
Significance and Impact on Prognosis [6] |
|---|---|---|---|
| Disease Drivers | |||
| JAK2 | PV *: 98% (~95% V617, ~4% exon 12) ET: 55% PMF: 60% |
V617F; Missense/indel in aa range: pp. 536–547 (NM_004972) | WHO/ICC criterion for diagnosis; intermediate prognosis with a heightened risk of thrombosis relative to CALR type 1 mutation carriers [6,13] |
| MPL | PV: 0% ET: 5–7%, PMF 7–10% |
S505G, S505N, S505C, L510P, del513, W515A, W515R, W515K, W515S, W515L, A519T, A519V, Y591D, W515-518KT. (NM_005373) | WHO/ICC criterion for diagnosis; intermediate prognosis with a heightened risk of thrombosis relative to CALR type 1 mutation carriers [6,13] |
| CALR | PV: 0% ET: 25–30% PMF: 20–30% |
Frameshift in exon 9 (NM_004343) | WHO/ICC criterion for diagnosis; CALR 1: enhanced OS and reduced thrombosis risk in comparison to those with JAK2 mutations and TN-PMF, as well as better OS than CALR type 2 mutation carriers [14,15,16]; CALR 2: lower OS than CALR 1 [17] |
| Clonal Drivers | |||
| DNMT3A | PV: 5–10% ET: 1–5% PMF: 8–12% |
Frameshift/nonsense/splice-site; missense in aa range: pp. 292–350, 482–614, 634–912 (NM_022552) | Inferior OS post-HCT [18] |
| IDH1 | PV: 1–2% ET: 1–2% PMF: 5–6% |
Frameshift/nonsense/splice-site in exon 11–12 (NM_015338) | HMR Inferior OS and reduced PFS post-HCT [8] |
| IDH2 | PV: 1–2% ET: 1–2% PMF: 5–6% |
Missense at R132 (NM_005896) | HMR Inferior OS and reduced PFS post-HCT [8] |
| ASXL1 | PV: 2–7% ET: 5–10% PMF: 15–35% |
Frameshift/nonsense/splice-site in exon 11–12 (NM_015338) | HMR Adverse impact, particularly in PMF; marked by poorer OS and LFS, including post-HCT [8] |
| EZH2 | PV: 1–2% ET: 1–2% PMF: 7–10% |
Frameshift/nonsense/splice-site; missense in SET domain (pp. 617–732) (NM_001203247) | HMR Inferior OS [8] |
| NRAS | PV: <2% ET: <2% PMF: 2–4% |
Missense at G12/G13/Q61 (NM_002524) | Inferior OS [19] |
| KRAS | PV: <2% ET: <2% PMF: 2% |
Missense at G12/G13/Q61 (NM_033360) | Similar to NRAS |
| CBL | PV: <2% ET: <2% PMF: 4% |
Missense in Linker/RING finger domains (pp. 345–434) (NM_005188) | Inferior OS post-HCT [18] |
| SRSF2 | PV: <2% ET: <2% PMF: 6–14% |
Missense/in-frame deletion involving P95 (NM_003016) | HMR in all MPNs Inferior OS and LFS; adverse prognosis in transformation [8] |
| U2AF1 | PV: <2% ET: <2% PMF: 7–10% |
Missense at S34/Q157 (NM_006758) | HMR Adverse prognosis in PMF and secondary AML; diminished OS post-HCT, with U2AF1 Q157 mutation associated with worse outcomes compared to U2AF1 S34 mutations or unmutated MF [18] |
| TP53 | PV: <2% ET: <2% PMF: 2–5% Increased frequency in advanced stages/post-MPN AML |
Frameshift/nonsense/splice-site; missense in aa range: pp. 72, 95–288, 337 (NM_001126112) | Higher likelihood of leukemic transformation [20] |
| TET2 | PV: 10–20% ET: 3–10% PMF: 10–20% |
Frameshift/nonsense/splice-site; aa range: pp. 1104–1481, 1843–2002 (NM_001127208) | No consensus impact on prognosis |
| SH2B3 (LNK) | PV: 2–9% ET: 1–3% PMF: 2–4% |
Frameshift/nonsense/splice-site; Missense at E208Q (NM_005475) [21] | Reported as potential driver in JAK2 negative MPN [22] |
| RUNX1 | PV: <2% ET: <2% PMF: 2–3% |
Frameshift/nonsense/splice-site, S73F, H78Q, H78L, R80C, R80P, R80H, L85Q, P86L, P86H, S114L, D133Y, L134P, R135G, R135K, R135S, R139Q, R142S, A165V, R174Q, R177L, R177Q, A224T, D171G, D171V, D171N, R205W, R223C (NM_001001890) | Frequent in leukemic transformation [23,24] |
| SF3B1 | PV: 2–3% ET: 2–5% PMF: 5–7% The possibility of mixed myelodysplastic component should be considered [3,4] |
Missense in terminal HEAT domains (pp. 529–1201) (NM_012433) | Adverse impact in ET [12] |
* Abbreviations: PV: Polycythemia Vera; ET: Essential Thrombocythemia; PMF: Primary Myelofibrosis; WHO: World Health Organization; ICC: International Consensus Classification; OS: overall survival; LFS: leukemia-free survival; HCT: hematopoietic cell transplantation; HMR: high-molecular-risk mutation; PFS: progression-free survival.