Alternative Splicing, a Driving Force in Acute Myeloid Leukaemia and How to Target it

Abstract

A cell contains a genetic code called DNA that stores all the biological information. To produce proteins from DNA messenger RNA (mRNA) is needed. Initially, mRNA is transcribed as a primary transcript called pre-mRNA, which has multiple coding regions separated by non-coding regions. In order to translate a protein from pre-mRNA, the non-coding regions have to be spliced out first. Splicing is performed by a complex of different proteins called the spliceosome, which consists of a few core proteins and splicing factors. After additional RNA processing, the mRNA is ready for translation into a protein. The human genome comprises roughly 20.000 to 25.000 protein-coding genes, however, together they encode over 90.000 different proteins. The diversity is caused by a process called alternative splicing (AS), where the non-coding and coding regions are spliced differently. This entitles that either coding regions are alternatively included/excluded or non-coding regions are retained, resulting in a mRNA isoform. These isoforms are then translated into different versions of the same protein (protein isoforms). Aberration in AS is often involved and critical for different cancers, such as acute myeloid leukaemia. This is a malignant disorder of the myeloid line of blood cells and is characterized by rapid expansion of abnormal blood cells and interferes with normal blood cell production. It is the most prevalent form of acute leukaemia, with around 20.000 cases and 12.000 deaths in the United States alone. Dysfunction of AS in cancer is often associated with mutations in splicing-regulating genes and can drive tumour pathogenesis and progression. Besides these mutations, recent research has shown that epigenetic influences play a role in the splicing aberrations. For example, tumour growth causes hypoxia due to lack of oxygen in the tumour microenvironment, which induces hypoxia dependent AS. The consequence of AS dysregulation is the generation of different isoforms of proteins exclusively expressed in cancer. But the expression of proteins that we see in a healthy cell is also altered and shifted to different isoforms not exclusive to cancer. The specific splicing pattern we see in cancer and the transcriptome landscape can form excellent targets for prognosis and anticancer treatment because of their distinction from healthy cells. In this review, we will explain how AS works, the exact effect it has on acute myeloid leukaemia, and its use in prognosis and therapy. We will also talk about the unanswered questions on AS in cancer, how treatment resistance is built up due to AS, and the current problems of targeting AS for potential anticancer treatment.