Non-Fusion Genes in Leukemia Translocations: A Brief Overview
While many leukemia-associated translocations result in fusion genes and subsequently, chimeric proteins with altered functions, some translocations disrupt genes without creating fusion products. These disruptions can still contribute to leukemia development through various mechanisms. Let’s explore some examples:
1. Deregulation of Gene Expression:
- Translocations affecting promoters or enhancers: Translocations can reposition genes near strong enhancers or promoters, leading to their overexpression. This can be seen in cases like the IGH-BCL2 translocation in follicular lymphoma, where the BCL2 gene (anti-apoptotic) comes under the influence of the IGH enhancer, causing its overexpression and promoting cell survival.
- Translocations disrupting repressor binding sites: Some translocations can remove or disrupt repressor binding sites within a gene’s regulatory region. This can lead to the loss of normal gene repression and subsequent overexpression.
2. Gene Disruption/Loss of Function:
- Translocations leading to truncation or deletion: Translocations can directly disrupt a gene’s coding sequence, leading to the production of a truncated or non-functional protein.
- Translocations affecting splicing: Translocation breakpoints within introns can disrupt splicing signals, leading to aberrant mRNA processing and potentially non-functional protein products.
Examples of genes commonly affected by these mechanisms:
- Tumor suppressor genes: Translocations affecting tumor suppressors like TP53, CDKN2A, or RB1 can lead to their inactivation, removing crucial cell cycle control and promoting uncontrolled proliferation.
- Transcription factors: Disruption of transcription factors involved in hematopoietic development or differentiation can contribute to leukemia development. For instance, translocations affecting RUNX1 or ETV6 can disrupt normal blood cell development.
- Cell signaling genes: Genes involved in cell signaling pathways, like NOTCH1 or FLT3, can be affected by translocations, leading to aberrant activation and promoting cell proliferation and survival.
It’s important to note that the specific consequences of a translocation depend on various factors, including the genes involved, the location of breakpoints, and the resulting changes in gene expression or function.