A UCLA Jonsson Comprehensive Cancer Center study found that removing a protein overexpressed in a rare and aggressive subtype of leukaemia can help slow cancer growth and increase survival rates.
The findings, published today in Leukemia, may help develop targeted therapies for cancers with high levels of IGF2BP3, particularly acute lymphoblastic and myeloid leukemias with chromosomal rearrangements in the mixed lineage leukaemia (MLL) gene.
IGF2BP3 binds to specific RNA molecules that carry genetic instructions for cancer-related proteins in these MLL-rearranged leukemias, significantly amplifying cancer development. Children and adults with this subtype have a poor prognosis and an increased risk of relapse following treatment.
“This type of leukemia is more aggressive because of its ability to divide and spread faster,” said senior author Dr Dinesh Rao.
“The disease can be very difficult to treat, even with new targeted immunotherapies like CAR T cell therapy and blinatumomab.”
Genetic mutations cause bone marrow stem cells to produce too many white blood cells, compromising the body’s ability to fight infection. Rao and his team previously identified IGF2BP3 as a factor in driving leukaemia development, particularly the MLL-rearranged subtype, by regulating various RNA messages.
Considering this, the researchers wondered if removing IGF2BP3 would stop leukaemia cell proliferation. Rao and his team used CRISPR-Cas9 gene editing to remove IGF2BP3 from MLL-leukemic mice and cell lines. They found striking effects on survival.
Approximately 75% of the leukemic mice with IGF2BP3 deletion lived longer, and 50% were leukemia-free. The team found that removing IGF2BP3 reduced the tumour burden of the mice fourfold, as measured by the weight of their spleens.
“By targeting this RNA-binding protein, we would be able to target the cancer cells directly and leave the healthy, non-cancerous cells alone.”
The team discovered that targeting IGF2BP3 did not impair normal blood development in mice; the blood system appeared intact when the protein was removed. Even mice lacking the protein developed normally.
“This was surprising to us because a lot of proteins that are important in cancer are also important in normal tissues,” said Rao.
“This is also an attractive target because we have made some real advances in understanding how it works in the cancer cells,” Rao added.
“We were able to pinpoint some important RNA molecules that it binds to, which encode other cancer-causing proteins. So if you can remove this protein, you’re able to modify the amount of other cancer-causing proteins,” said Rao.
While the team focused on MLL leukemias, IGF2BP3 is highly expressed in 15–20% of other cancers, including glioblastoma, pancreatic cancer, lung cancer, and melanoma.
The next step for researchers is to see if removing the protein has the same effect on other cancers, and to develop small-molecule and RNA-based therapeutics to disrupt the protein’s function.
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