Molecular mechanisms by which splice modulator GEX1A inhibits leukemia development and progression

We examined the anti-leukemic effects of a natural splice modulator, GEX1A, through comparing RNA expression and splicing changes observed between pre-determined GEX1A-sensitive cells and GEX1A-resistant human leukemic cell lines. We found that GEX1A downregulates many pro-survival genes in the GEX1A-sensitive cell types through intron retention and other althernative splicing changes, notably in the FASTK, MCL1, and FLT3 transcripts. Additionally, GEX1A lead to an upregulation of many pro-apoptotic factors within the sensitive cell types, such as FAS, TNFRSF10B, CDKN1A, and TP53INP1. Overall, 573 genes were differentially expressed in the sensitive cell types only, whereas 604 genes were differentially expressed in the resistant cell types only. This study demonstrates that GEX1A selectively kills certain leukemic cells via apoptotic induction, notably through pro-survival factor downregulation and pro-apoptotic factor upregulation. Comparison of 2 GEX1A-sensitive human leukemic cell types (Molm-13, MV4:11) to 2 GEX1A-resistant cell types (HL-60, K562), both vehicle-treated and GEX1A-treated at 100 nM for 6 hrs.