Table 2.
Some clinically relevant somatic mutations detectable in myeloid neoplasms based on oncogenic potential and risk to transform to secondary acute myeloid leukemia (sAML).
| Myeloid Neoplasm | Clinically Relevant Somatic Mutations | ||
|---|---|---|---|
| Early (CHIP-Like) | Specific/Driver | Late/Transforming | |
| MDS [49,50,51,52] | TET2, DNMT3A, IDH1/2 * | SF3B1, SRSF2, U2AF1, ZRSR2 ** | ASXL1 ***, RUNX1, TP53, EZH2, SETBP1, STAG2, NPM1, FLT3, PTPN11, N/KRAS, CBL, WT1, PHF6 |
| PV | TET2 ****, DNMT3A, ASXL1 § | JAK2 V617F, JAK2 exon 12 | TP53, RUNX1, SRSF2, U2AF1, IDH1/2, CBL, EZH2, FLT3, N/KRAS, NPM1, ETV6, SETBP1 [13,51,53,54] |
| ET | TET2, DNMT3A, ASXL1 | JAK2 V617F, CALR, MPL | |
| PMF | TET2, DNMT3A, ASXL1 | JAK2 V617F, CALR, MPL | |
| CMML [55,56,57,58] | TET2, SRSF2, ASXL1, DNMT3A§§ | TET2, SRSF2, ASXL1, N/KRAS, CBL, SETBP1, EZH2 | RUNX1, N/KRAS, CBL, EZH2, U2AF1, SETBP1§§§ |
| CML | TET2, DNMT3A, ASXL1 | BCR-ABL1 | BCR-ABL1 mutations, ASXL1, IKZF1, TP53, RUNX1, SETD1B |
| AML [59,60] | DNMT3A, TET2, ASXL1, IDH1/2 * | PML-RARA, MYH11-CBFB, RUNX1-RUNX1T1, MLLT3-KMT2A, DEK-NUP214, RUNX1, NPM1, CEBPA, GATA2 | FLT3, N/KRAS, KIT, PTPN11, TP53, PHF6, SRSF2, STAG2, EZH2, RAD21 |
| AdvSM/MCL [38] | TET2, ASXL1, SRSF2 | KIT D816V/H/Y | RUNX1, CBL, N/KRAS, SRSF2, IDH1/2 |
* Although IDH1/2 mutations are associated with an unfavorable clinical outcome in myelodysplastic syndrome (MDS), they appear to be early events in the clonal evolution in MDS and acute myeloid leukemia (AML). In MPN, IDH1/2 mutations usually appear as late events leading to leukemic transformation. Of note is that these mutations have not been identified in the context of CHIP/ARCH [19,61]. ** Although the SF3B1 mutation shows a clear association with the presence of ring sideroblasts in MDS, other mutations are not specific for MDS and appear at various frequencies across other myeloid malignancies. In MDS, they represent most frequently mutated genes and are usually detectable in the founding clone. These mutations are listed here as driver mutations, but not under CHIP-like mutations, because in the context of unexplained cytopenia, their presence is highly predictive of development of a myeloid neoplasm within 5 years (95%) [62]. *** ASXL1 gene mutations are commonly found in MDS patients. As in other myeloid malignancies these mutations are associated with an unfavorable outcome. Although they are found at similar frequencies in MDS and post-MDS sAML, they are more often sub-clonal mutations and were therefore marked here as late events [50]. **** TET2 mutations can both precede and follow the acquisition of JAK2 V617F in MPN. Ortmann et al. postulated that the order of acquisition of JAK2 and TET2 mutations has an effect on the phenotype, and that patients who acquire JAK2 V617F mutation first and TET2 mutation at a later time point are more likely to present with PV and have an increased risk of thrombosis [63]. § ASXL1 mutations can occur as early events, following the acquisition of JAK2 V617F/CALR mutations in MPN or as separate clones in MPN as demonstrated by Lundberg et al. [13]. They were found at higher frequency in post-PV and post-ET myelofibrosis, indicating their role in disease progression in MPN. §§ These four mutations were described by Patel et al. as ancestral events in the clonal evolution of CMML [56]. All of them, except DNMT3A, can also appear in sub-clones, indicating that they can also be late events in the clonal evolution of CMML. Some authors consider TET2- and ASXL1 mutations to be driver mutations in CMML due to their high frequency among the reported cases, and in particular the combination of TET2 and SRSF2 mutations which is highly prevalent in CMML. §§§ Despite many articles describing the genetic basis of CMML, no mutation was clearly associated with disease progression. RUNX1 is more frequently detected in post-CMML sAML than in CMML, however due to its high frequency in CMML the difference was not statistically significant [55]. Abbreviations: MDS, myelodysplastic syndromes; PV, polycythemia vera; ET, essential thrombocythemia; PMF, primary myelofibrosis; CMML, chronic myelomonocytic leukemia; CML, chronic myeloid leukemia; MPN, myeloproliferative neoplasms; AdvSM, advanced systemic mastocytosis; MCL, mast cell leukemia; CHIP, clonal hematopoiesis of indeterminate potential; ARCH, age-related clonal hematopoiesis.