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Abstract Background Gene mutation is an important mechanism of myeloid leukemogenesis. However, the number and combination of gene mutated in myeloid malignancies is still a matter of investigation. Methods We searched for mutations in the ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, RUNX1, TET2 and WT1 genes in 65 myelodysplastic syndromes (MDSs) and 64 acute myeloid leukemias (AMLs) without balanced translocation or complex karyotype. Results Mutations in ASXL1 and CBL were frequent in refractory anemia with excess of blasts. Mutations in TET2 occurred with similar frequency in MDSs and AMLs and associated equally with either ASXL1 or NPM1 mutations. Mutations of RUNX1 were mutually exclusive with TET2 and combined with ASXL1 but not with NPM1. Mutations in FLT3 (mutation and internal tandem duplication), IDH1, IDH2, NPM1 and WT1 occurred primarily in AMLs. Conclusion Only 14% MDSs but half AMLs had at least two mutations in the genes studied. Based on the observed combinations and exclusions we classified the 12 genes into four classes and propose a highly speculative model that at least a mutation in one of each class is necessary for developing AML with simple or normal karyotype.

Importance of the Field: The development of targeted anticancer therapies stems from advances in molecular biology. New agents range from antibodies that form complexes with antigens on the surface of the cancer cell to small molecules that have been engineered to block key enzymatic reactions. The interaction of the antibody or drug with its target inhibits key pathways involved in cell proliferation or metastasis, or activates pathways leading to cell death. Such pathways constitute ideal pharmacological targets. Clinical benefits from these novel therapeutic strategies are striking for patients with metastatic diseases., Areas Covered: This review analyses the main toxicities among most common targeted therapies that have been approved by the FDA or European Medicines Agency for their clinical utilisation in solid tumours treatment., What the Reader Will Gain: Here, the main toxicity and safety data among new anticancer targeted therapies are described. Data are organised through the pathways targeted by the drugs., Take Home Message: The emergence of new targeted anticancer therapies promises more efficient and less toxic therapies. Generally, they are well tolerated, toxicities are commonly mild to moderate and can be handled rapidly. However, if most of these adverse events are manageable, life threatening and fatal complications can still occur.