Transcription factors can also have a critical regulatory role in the splicing process and development of chemoresistance. Wilms tumor 1 (WT1) is a zinc finger transcription factor of important prognostic significance in AML with four predominant splice isoforms, one of which represses transcription of the SRPK1 splice factor and alters VEGF splicing, promoting production of the anti-angiogenic VEGF-A
165b isoform [
45]. While WT1 was originally identified as a tumor suppressor of kidney cancer, its critical role in AML development in transgenic mice transduced with AML1-ETO [
46], resistance to death stimuli [
47], and importance as a prognostic marker of patient relapse and survival [
48] demonstrate its functions as an oncogene in AML. WT1 has been shown to interact directly with the splice factors RBM4, U2AF2, and WTAP in an isoform-dependent manner, which can influence splicing outcomes of their target transcripts [
45]. In fact, knockdown of WT1 expression in AML cell lines promoted alternative splicing events affecting approximately 1200 genes [
47]. E2F transcription factor 1 (E2F1) is another transcription factor that influences apoptotic susceptibility of tumor cells by regulating alternative splicing of apoptotic genes [
49]. E2F1 has a role in induction of apoptosis caused by DNA damaging agents, by upregulating expression of the splicing factor SC35 (U2AF1) which promotes selection of the pro-apoptotic variants of FLICE-like inhibitory protein (c-FLIP), CASP8, CASP9, and BCL-X [
50]. Yet, while E2F1 may be an important tumor suppressor, when this transcription factor interacts with cofactors commonly expressed by tumor cells with defective cell death signaling pathways, it participates in feedback loops that can contribute to tumor aggressiveness and chemoresistance [
51]. It was shown that knockdown of E2F1 resulted in approximately a 50 % decrease of cell viability in chemoresistant lung adenocarcinoma cells exposed to multiple therapeutics [
52]. Therefore, E2F1 molecular targeting may be a beneficial therapeutic strategy for certain aggressive tumor phenotypes.