Table 1.
Overview of the most frequent mutations found in MPNs and post-MPN AML
| Gene | Most frequent mutation (types) | Mutation frequency | References | |||
|---|---|---|---|---|---|---|
| ET | PV | (P)MF | Post-MPN AML | |||
| MPN phenotypic driver mutations | ||||||
| JAK2 | Heterozygous and homozygous (acquired uniparental disomy) exon 12 and exon 14 mutations. V617F, located in the repressive JH2 domain, is the most frequent mutation. Also, gene/chromosomal duplications are found. | 50%–60% | 95% | 50%–60% | 37%–60% | Scott et al. 2007; Abdel-Wahab et al. 2010; Zhang et al. 2012; Vannucchi et al. 2013; Guglielmelli et al. 2014; Lundberg et al. 2014; Tefferi et al. 2016a,b; Lasho et al. 2018 |
| CALR | Heterozygous insertion and/or deletions in exon 9, resulting in a +1 base pair frameshift and a novel carboxyl terminus. | 26% | <1% | 18%–32% | 21%–25% | Guglielmelli et al. 2014; Lundberg et al. 2014; Rampal et al. 2014; Tefferi et al. 2016a,b: Lasho et al. 2018 |
| MPL | Heterozygous missense mutations, W515L/K most frequent, resulting in constitutive activation of the receptor. | 4% | <1% | 6%–9% | 8%–13% | Zhang et al. 2012; Vannucchi et al. 2013; Lundberg et al. 2014; Guglielmelli et al. 2014; Tefferi et al. 2016a,b; Lasho et al. 2018 |
| DNA methylation | ||||||
| TET2 | Heterozygous or homozygous loss-of-function mutations in its catalytic domain, causing reduced conversion of methylated to hydroxymethylated cytosines. | 7%–16% | 19%–22% | 10%–18% | 19%–28% | Abdel-Wahab et al. 2010; Zhang et al. 2012; Vannucchi et al. 2013; Lundberg et al. 2014; Tefferi et al. 2016a,b; Lasho et al. 2018; Venton et al. 2018 |
| IDH1a/ IDH2a | Heterozygous missense mutations in the active catalytic site, IDH1: R132, IDH2: R140 and R172, causing acquisition of the ability to convert αKG into 2-hydroxyglutatate. | 1% | 2% | 0%–6% | 19%–31% | Abdel-Wahab et al. 2010; Pardanani et al. 2010; Tefferi et al. 2010, 2016a,b; Zhang et al. 2012; Vannucchi et al. 2013; Guglielmelli et al. 2014; Lundberg et al. 2014; Rampal et al. 2014; Lasho et al. 2018; Venton et al. 2018 |
| DNMT3A | Mutations in DNMT3A in MPN occur as nonsense/frameshift mutations in addition to missense mutations (including at R882, which is located in the methyltransferase domain), resulting in reduced methyltransferase activity. | 0%–9% | 0%–7% | 3%–15% | 2%–14% | Abdel-Wahab et al. 2011; Lin et al. 2011; Stegelmann et al. 2011; Zhang et al. 2012; Vannucchi et al. 2013; Lundberg et al. 2014; Wang et al. 2014; Tefferi et al. 2016a,b: Lasho et al. 2018; Venton et al. 2018 |
| Chromatin modification | ||||||
| ASXL1a | Heterozygous nonsense and frameshift mutations in exon 12 leading to loss of its PHD domain. | 1%–11% | 3%–12% | 18%–37% | 17%–47% | Tefferi et al. 2016a,b, 2018d; Lasho et al. 2018; Vannucchi et al. 2013; Abdel-Wahab et al. 2010; Zhang et al. 2012; Lundberg et al. 2014; Guglielmelli et al. 2014; Rampal et al. 2014; Venton et al. 2018 |
| EZH2a | Heterozygous/homozygous/hemizygous loss-of-function mutations that disrupt or delete the catalytic SET2 domain. | 1%–3% | 0%–3% | 0%–9% | 13%–15% | Vannucchi et al. 2013; Guglielmelli et al. 2014; Lundberg et al. 2014; Tefferi et al. 2016a,b; Lasho et al. 2018; Venton et al. 2018 |
| RNA splicing | ||||||
| SRSF2a | Heterozygous missense mutations and small in-frame deletions around hotspot P95, affecting the preferred RNA recognition sequence (wild-type GGNG and CCNG, mutant GGNG) in RNA exon splicing enhancers. | 2% | 3% | 8%–18% | 13%–22% | Zhang et al. 2012; Vannucchi et al. 2013; Guglielmelli et al. 2014; Rampal et al. 2014; Tefferi et al. 2016a,b, 2018d; Lasho et al. 2018; Venton et al. 2018 |
| U2AF1a | Heterozygous missense mutations around hotspots S34 and Q157, which alter the preferred –3 (C/A >> T, S34F/Y) or +1 (G >> A, Q157P) nucleotides flanking the AG of the 3′ splice site. | 1% | <1% | 16% | 5%–6% | Zhang et al. 2012; Tefferi et al. 2016a,b, 2018; Lasho et al. 2018d |
| ZRSR2 | Hemizygous frameshift and nonsense mutations. Loss-of-function mutations. | 3% | 5% | 10% | 2% | Zhang et al. 2012; Tefferi et al. 2016a,b |
| SF3B1 | Heterozygous missense mutations in exons 14–16, hotspot K700E most frequent mutation. Most commonly mutated in MDS/MPN-RS-T 80%. | 5% | 3% | 9%–10% | 4%–7% | Dunbar et al. 2008; Makishima et al. 2009; Muramatsu et al. 2010; Malcovati et al. 2011; Papaemmanuil et al. 2011; Yoshida et al. 2011; Zhang et al. 2012; Tefferi et al. 2016a,b, 2018d; Lasho et al. 2018 |
| Signaling | ||||||
| LNK | Mostly heterozygous missense substitutions targeting the pleckstrin homology domain in 50% of cases. | 1%–3% | 0%–9% | 0%–6% | 11% | Lundberg et al. 2014; Tefferi et al. 2016a,b; Lasho et al. 2018 |
| CBL | Homozygous missense substitutions located in the RING and linker domain reducing E3 ligase activity. | 0%–1% | 0%–2% | 0%–6% | 4% | Grand et al. 2009; Vannucchi et al. 2013; Lundberg et al. 2014; Tefferi et al. 2016a,b; Lasho et al. 2018 |
| NRAS/KRAS | Heterozygous missense substitutions at codons 12, 13, and 61 causing reduced intrinsic GTP hydrolysis and resistance to GAPs. | <1% | 0%–1% | 3%–4% | 7%–15% | Zhang et al. 2012; Lundberg et al. 2014; Tefferi et al. 2016a,b; Lasho et al. 2018; Venton et al. 2018 |
| PTPN11 | Heterozygous missense mutations in the Src-homology 2 (N-SH2) and phosphotyrosine phosphatase (PTP) domains causing increased phosphatase activity. | 0%–2% | <1% | 0%–2% | 6%–8% | Ding et al. 2009; Lundberg et al. 2014; Rampal et al. 2014; Tefferi et al. 2016a,b; Lasho et al. 2018 |
| Transcription factors | ||||||
| RUNX1 | Missense, frameshift, and nonsense mutations causing loss of function, and may act in a dominant-negative fashion over wild-type RUNX1. Both homozygous and heterozygous mutations are found. | 0%–2% | 0%–2% | 3%–4% | 4%–13% | Ding et al. 2009; Zhang et al. 2012; Lundberg et al. 2014; Tefferi et al. 2016a,b: Lasho et al. 2018; Venton et al. 2018 |
| NFE2 | Mostly heterozygous frameshift mutations causing increased expression and protein levels of wild-type NFE2. | <1% | 2%–3% | 0%–3% | <1% | Jutzi et al. 2013; Lundberg et al. 2014 |
| DNA repair response/stress signaling | ||||||
| TP53 | Mostly missense mutations, both alleles affected. Possibly loss-of-function, gain-of-function, and/or dominant-negative. | 2%–6% | 1% | 1%–3% | 11%–36% | Harutyunyan et al. 2011; Zhang et al. 2012; Lundberg et al. 2014; Rampal et al. 2014; Tefferi et al. 2016a,b; Lasho et al. 2018; Venton et al. 2018 |
| PPM1D | Heterozygous exon 6 mutations causing loss of carboxy-terminal degradation domain. | 2% | 1% | 1% | NA | Grinfeld et al. 2018 |
MPN, Myeloproliferative neoplasm; AML, acute myeloid leukemia; ET, essential thrombocythemia; PV, polycythemis vera; (P)MF, (primary) myelofibrosis; ASXL1, EZH2, SRSF2, IDH1/2, U2AFQ157, GTPase-activating proteins; αKG, α-ketgoglutarate; MDS/MPN-RS-T, myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis; NA, not assessed; PHD, plant homeodomain.
aHigh molecular risk mutations in (primary) myelofibrosis (Vannucchi et al. 2013; Guglielmelli et al. 2018).