Mechanistically, we showed that SACLAC treatment led to reduced levels of splicing factor SF3B1 and alternative Mcl-1 mRNA splicing in multiple human AML cell lines.
This drug is approved for AML patients with MDS-related changes and therapy-related AML, both of which are frequently associated with complex karyotype.
Patient was initially diagnosed with low-risk myelodysplastic syndrome-refractory cytopenias and multilineage dysplasia (MDS-RCMD), progressed to AML after failing hypomethylating agent therapy.
Patients with double mutation or isolated SF3B1 mutation were less likely to be diagnosed with acute myeloid leukemia than patients with isolated TET2 mutation.
Metformin, a widely used antidiabetic drug, has previously been demonstrated to exert anti-cancer effects in certain hematological malignancies, but its effects on the transformation of myelodysplastic syndromes to acute myeloid leukemia (AML-MDS) remain unclear.
AML with LM-CH was found in 40 patients (23%) and was associated with clonal hematopoiesis of indeterminate potential years before AML, older age, secondary AML and more frequent MDS-type co-mutations (TET2, RUNX1 and EZH2).
Results confirm high frequencies of RAS and other activated signaling mutations (10/12 AMLs) and identify new recurrent mutations in splicing factors (5/12 AMLs in SF3B1 and 2/12 AMLs in U2AF1), IKZF1 (3/12 AMLs), and TP53 (3/12 AMLs).
The SRSF2 mutation strongly correlated with old age (P < 0.001), while the mutation status of SF3B1 did not affect overall survival (OS), progression-free survival (PFS), or acute myeloid leukemia (AML) transformation.
High-resolution melting analysis (HRMA) was established to detect the mutation hotspots (codon E622, H662, K666, and K700) of SF3B1 gene in 275 AML and 81 CML patients.
Over the past few years, large-scale genomic studies of patients with myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) have unveiled recurrent somatic mutations in genes involved in epigenetic regulation (DNMT3A, IDH1/2, TET2, ASXL1, EZH2 and MLL) and the spliceosomal machinery (SF3B1, U2AF1, SRSF2, ZRSR2, SF3A1, PRPF40B, U2AF2, and SF1).
In multivariate analysis including established risk factors, SF3B1 mutations were found to be independently associated with better overall survival (hazard ratio = 0.15, P = .025) and lower risk of evolution into AML (hazard ratio = 0.33, P = .049).