New research led by scientists from UCLA has shown that the deletion of an RNA-binding protein can significantly increase survival rates from an aggressive subtype of leukaemia. These findings reveal significant insights into posttranscriptional regulation in leukaemia and highlight a potential therapeutic target for this disease.
RNA-binding proteins in leukaemia
The study, done in mice, followed up on previous findings. Emerging evidence suggests that RNA-binding proteins (RBPs) are key to regulating gene expression during leukaemia. RBPs play a major role in the post-transcriptional control of RNA molecules, controlling processes from splicing to translation.
In 2016, the team identified the oncofoetal RNA-binding protein insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3) as an important regulator of gene expression in leukemic cancers. IGF2BP3 is usually present at low levels in healthy adult tissues where it recruits target transcripts to cytoplasmic protein-RNA complexes. High levels of the protein correlate with low patient survival. However, the extent of IGF2BP3’s role in leukaemia was still unclear. Now, the group has discovered that IGF2BP3 strongly amplifies leukemogenesis and its deletion can greatly attenuate disease.
Mixed lineage leukaemia rearrangements
Chromosomal rearrangements of the mixed lineage leukaemia gene (MLL) characterise leukemic cancers. Such MLL rearrangements are repeatedly found in acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML) and acute leukaemia of ambiguous lineages. Here, researchers found that IGF2BP3 can act as a marker of disease aggressiveness in B-ALL.
MLL can fuse with a translocation partner gene to produce the fusion protein MLL–AF4. MLL–AF4 driven leukaemia has a unique gene expression profile which is characterised by high levels of transcriptional dysregulation. The study found that IGF2BP3 is overexpressed in MLL-translocated leukaemia, and positively regulates MLL-Af4 transcriptional targets. This greatly speeds up cancer progression, which perhaps explains the correlation with diminished patient survival rates.
Impact of IGF2BP3 deletion
The research team explicitly tested the requirement for Igf2bp3 in a model of MLL-Af4-driven leukemogenesis in mice. They found that Igf2bp3 knockout (I3KO) MLL-Af4 mice survived significantly longer and became leukemic much later than control mice. Interestingly, 50% of the mice were actually leukaemia free after the Igf2bp3 deletion.
Patients suffering from leukaemia produce too many white blood cells (WBCs), which affects their ability to fight infection. The over-production leads to large numbers of WBCs accumulating in the spleen and bone marrow. To see what effect IGF2BP3 has on this process, the researchers compared WBC numbers in control and I3KO mice. The I3KO mice showed a 30-fold reduction in CD11b+ cells in the spleen and a 2.5-fold reduction in the bone marrow, resulting in significantly smaller tumours.
Leukaemia-initiating cells (LICs) possess stem cell properties and are known to play a key role in disease development. In I3KO mice, LIC numbers decreased by tenfold in the spleen and fivefold in the bone marrow after 14 weeks. Igf2bp3 deletion not only reduced LIC numbers but it also impaired function, as LICs lose their ability to self-renew.
LICs have the capability to produce cancerous cells in bulk. They also tend to persist throughout treatments, leading to patients relapsing. Therefore, the role of IGF2BP3 in LICs is of great interest. However, human LICs in MLL-Af4 are less understood than those of mice, so researchers will need to carry out further studies to discover whether the interactions are the same.
Interestingly, throughout the study researchers found that IGF2BP3 was not necessary for normal haematopoiesis in mice, with the I3KO mice showing minimal changes in their blood development.
“This was surprising to us because a lot of proteins that are important in cancer are also important in normal tissues,” senior author Dr. Dinesh Rao said.
As patients with MLL-rearranged leukaemia have poor outcomes and high risk of relapse, these findings suggest that IGF2BP3 may be an attractive future therapeutic target. Its apparent lack of importance in healthy tissues, its central role in cancer development, and its appearance in other cancer types makes it a popular subject of future research.
“These results really highlight IGF2BP3 as an attractive and valuable therapeutic target,” said lead author Tiffany Tran. “By targeting this RNA-binding protein, we would be able to target the cancer cells directly and leave the healthy, non-cancerous cells alone.”