Functional categories | Consequences of genetic alterations |
---|---|
Signal transduction genes | Mutations in FLT3, a class III tyrosine kinase receptor, or NRAS, KRAS, c-KIT, PTPN11 confer proliferative advantages through hyperactivation of related signal cascades such as JAK/STAT, PI3K/AKT/NFKB and RAF/MEK/ERK. |
Myeloid transcription factors (TF) | Mutations in myeloid TF (AML1, CEBPA, RUNX1) or genetic fusions following chromosomal rearrangements t(8;21)(q22;q22) RUNX1-RUNX1T1, AML1-ETO, t(15;17)(q24;q21) PML-RARA, or inv(16) (p13.1q22) and t(16; 16)(p13.1;q22) CBFB-MYH11, are events responsible for transcriptional deregulation and affect correct hematopoiesis. |
Tumor Suppressor Genes | Mutations in P53, WT1 or PHF6 can deregulate normal transcription activity and alter checkpoints responses of the cell (for instance mutated P53 blocks the degradation of PTEN increasing proliferative action) |
Spliceosome Complex | Mutations in components of the spliceosome complex such as SRSF2, SF3B1, U2AF1 and ZRSR2 can alter proper mRNA maturation with intron retention or exon skipping events. |
Multifunctional shuttling protein | Mutations in nucleophosmin (NPM1) are responsible for its anomalous cytoplasmic localization and consequently of the proteins that interact with it, for instance ARF, influencing the ribosome biogenesis and P53 stability. |
Cohesin Complex | Mutations in SMC1A, SMC3, STAG2, RAD21 affect normal chromosomal segregation and transcriptional regulation by increasing chromatin accessibility and increasing the binding of TF AML1 and GATA2 with consequent proliferative increase and decrease in cell differentiation. |
DNA methylation genes | Mutations in genes involved in DNA methylation such as DMNT3A, TET2, IDH1/2 can alter epigenetic regulation |
Chromatin modifiers | Epigenetic homeostasis can be perturbed in relation to mutations in genes involved in chromatin modifications; for instance ASXL1, EZH2, MLL partial duplication or t(9;11)(p22;q23) KMT2A-MLLT3 alias MLL-AF9 gene fusions. |