Table 2.

High-risk mutations, their functional class and mechanisms of leukemogenesis.

High-risk mutations	Functional class	Mechanisms of leukemogenesis	Incidence in AML
FLT3, KRAS, NRAS, KIT	Signaling and kinase pathway	These mutations lead to the aberrant activation and proliferation of cellular signaling pathways.	~2/3 of AML cases
DNMT3A, ASXL1	Epigenetic modifiers (DNA methylation and chromatin modification)	Felt to be inciting mutations in leukemogenesis and are often found in age-related clonal hematopoiesis. These mutations likely promote clonal outgrowth, but require additional mutations to initiate leukemic transformation.Of note: DNMT3A mutations in conjunction with mutation NPM1 confers particularly poor prognosis. NPM1participates in a variety of cellular functions, which include protein formation, ribosome biogenesis, DNA replication, and the cell cycle.	~1/2 of AML cases
SRSF2, SF3B1, U2AF1, and ZRSR2	Spliceosome complex	Spliceosome complex is important for RNA splicing of mRNA precursors. Mutations in RNA spliceosomes causes mis-splicing of mRNA precursors leading to abnormal epigenetic regulation, transcription, and genome integrity, ultimately leading to cancer. These are often seen in older individuals with less proliferative disease.	~1/10 of AML cases
RUNX1	Transcription factors	This is an important core-binding factor family of transcription factors involved in embryogenesis of HSC generation and regulation of HSC differentiation and homeostasis. When mutated, may lead to a stem cell phenotype characterized by early HSC exhaustion.	~1/10 of AML cases
TP53	Tumor suppressors	Tumor suppression occurs via apoptosis, DNA repair and cell cycle arrest/senescence, and when disrupted, will lead to survival of cancerous cells.	~1/6 of AML cases

AML, acute myeloid leukemia; HSC, hematopoietic stem cells.