Removal of Overexpressed Protein Could Improve Survival in Aggressive Leukemia

Immature blood cells in leukemia.
Immature blood cells in leukemia [Source: toeytoey2530/Getty Images]

Removal of an overexpressed protein known as IGF2BP3 using CRISPR-Cas9 in mice with aggressive leukemia led to improved survival and at least half the mice becoming disease free, show results from a study led by researchers at the UCLA Jonsson Comprehensive Cancer Center.

Although the work is still at an early stage, the team believes it shows that targeting IGF2BP3 could also be a good strategy for human patients with aggressive leukemia, particularly acute lymphoblastic and myeloid leukemias that are characterized by chromosomal rearrangements in the MLL gene.

Although therapy choices have improved, leukemia patients with rearrangements in the MLL gene (also known as KMT2A) have poor outcomes, a high chance of relapse and often show resistance to new targeted therapies.

The RNA-binding protein IGF2BP3 is overexpressed in patients with this kind of cancer. As described in the journal Leukemia, lead author Dinesh Rao, an associate professor of pathology and laboratory medicine at the David Geffen School of Medicine at UCLA, and colleagues explain that this protein attaches to mRNA encoding proteins needed for leukemia progression and, in so doing, amplifies cancer development.

The team found that IGF2BP3 seems to play a strong role in regulating leukemia development in those with the most commonly seen translocation mutation of MLL in this kind of cancer, known as MLL-AF4.

“This type of leukemia is more aggressive because of its ability to divide and spread faster,” said Rao, in a press statement. “The disease can be very difficult to treat, even with new targeted immunotherapies like CAR T-cell therapy and blinatumomab.”

Rao and team carried out a study in a mouse model of MLL leukemia and in cancer cell lines to assess if using the gene editing tool CRISPR-Cas9 to remove the IGF2BP3 protein could have a beneficial effect on cancer progression.

They found that 75% of the mice with deleted IGF2BP3 had an increase in overall survival and 50% became leukemia free after the treatment. Tumor-burden in the animals also decreased fourfold.

Notably, the researchers also assessed whether removing this protein had any negative effects on the blood system, but say that even mice with no IGF2BP3 at all seemed to develop normally.

“This was surprising to us because a lot of proteins that are important in cancer are also important in normal tissues,” said Rao. “We have made some real advances in understanding how it works in the cancer cells. 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.”

While it will be some time before this work could reach the clinic, the researchers plan to continue their work on IGF2BP3 in leukemia and assess if human treatments could be possible. Therapeutic gene editing for other conditions is currently being tested in human trials, but has yet to be approved for any indication.

“These results really highlight IGF2BP3 as an attractive and valuable therapeutic target,” said lead author Tiffany Tran, a graduate student researcher in UCLA’s molecular, cellular and integrative physiology interdepartmental doctoral program. “By targeting this RNA-binding protein, we would be able to target the cancer cells directly and leave the healthy, non-cancerous cells alone.”

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