Avapritinib demonstrated strong clinical activity in patients with SRSF2, ASXL1 and/or RUNX1
mutation positive genotypes, who historically have particularly poor prognoses.
The mutations in AML involve epigenetic modifiers (TET2, IDH1/IDH2, DNMT3A, ASXL1, KMT2A, EZH2), activated signaling pathway (FLT3, KRAS, NRAS, KIT), tumor suppressor genes (TP53, WT1), RNA splicing (SF3B1), nucleophosmin mutation (NPM1), and genes coding for transcription-differentiation (CEBPA, RUNX1
) (Figure 1) (6-8).
(21) DDX41 germline mutation is considered as a founder mutation, with other additional mutations such as TP53 and RUNX1
The data suggest that one mutation in any of these pathways is sufficient for the pathogenesis of AML and that certain mutations common in AML (e.g., in DNMT3A, NPM1, CEPBA, IDH1/2, and RUNX1
) play a role in the initiation of AML similar to the fusion genes.
Eighty-eight transcription regulators were found in the adipose tissue between 18 vs 24, KLF5, one of activated transcription regulators, which is relevant to cancer, cellular development, cellular growth and proliferation, and this regulator is unregulated FAM110A, MYC, DUSP1, ACTA2, NOTCH1 and PREB, down regulated RUNX1
Next-generation sequencing (NGS) was available in seven patients using a custom-designed 49 genes' panel (Ion S5™ System, Thermo Fisher, San Diego, CA, USA), including the entire coding region of ASXL1, ASXL2, BCOR, BCORL1, BIRC3, BRAF, CALR, CBL, CDKN2A, CSF3R, CSMD1, DNMT3A, ETNK1, ETV6, EZH2, FBXW7, FLT3, GATA2, IDH1, IDH2, IL7R, JAK1, JAK2, JAK3, KIT, KRAS, MPL, MYD88, NOTCH1, NRAS, PAX5, PDGFRA, PDGFRB, PHF6, PIGA, PTEN, PTPN11, RUNX1
, SETBP1, SETD2, SF3B1, SH2B3, SRSF2, STAG2, TET2, TP53, U2AF1, WT1 , and ZRSR2 , with a median depth of x2000.
Estas incluyen IRF4, BATF y RUNX1
(Kurebayashi et al., 2000).
Non-syndromic thrombocytopenias with increased risk of hematologic malignancy are associated with mutations in RUNX1
, ANKRD26 and ETV6, which lead to thrombocytopenia with mild to moderate bleeding and no other syndromic associations.
Mantel et al., "Transcription factors RUNX1
and RUNX3 in the induction and suppressive function of Foxp3+ inducible regulatory T cells," The Journal of Experimental Medicine, vol.
Lu et al., "Runx1
directly promotes proliferation of hair follicle stem cells and epithelial tumor formation in mouse skin," Molecular and Cellular Biology, vol.
Deng et al., "LincRNA-uc002yug.2 involves in alternative splicing of RUNX1
and serves as a predictor for esophageal cancer and prognosis," Oncogene, vol.
Tang et al., "MicroRNA-9 regulates the differentiation and function of myeloid-derived suppressor cells via targeting Runx1
," Journal of Immunology, vol.