Eliminating RNA-binding protein improves survival in aggressive leukemia
Scientists find that removing IGF2BP3 selectively targets cancer cells
while leaving healthy cells alone

Date:
July 29, 2021
Source:
University of California - Los Angeles Health Sciences
Summary:
Removing a protein that is often overexpressed in a rare and
aggressive subtype of leukemia can help to slow the cancer's
development and significantly increase the likelihood of survival,
according to a new study in mice.



FULL STORY ========================================================================== Removing a protein that is often overexpressed in a rare and aggressive
subtype of leukemia can help to slow the cancer's development and
significantly increase the likelihood of survival, according to a study
in mice led by scientists at the UCLA Jonsson Comprehensive Cancer Center.


==========================================================================
The research, published today in the journal Leukemia, could aid in the development of targeted therapies for cancers that have high levels of
the RNA- binding protein IGF2BP3 -- especially acute lymphoblastic and
myeloid leukemias that are characterized by chromosomal rearrangements
in the mixed lineage leukemia (MLL) gene.

In these MLL-rearranged leukemias, IGF2BP3 attaches to certain RNA
molecules that carry genetic instructions for cancer-related proteins,
markedly amplifying cancer development. Children and adults diagnosed
with this subtype have a poor prognosis and a high risk of relapse
after treatment.

"This type of leukemia is more aggressive because of its ability to
divide and spread faster," said senior author Dr. Dinesh Rao, a member
of the Jonsson Cancer Center and an associate professor of pathology
and laboratory medicine at the David Geffen School of Medicine at
UCLA. "The disease can be very difficult to treat, even with new
targeted immunotherapies like CAR T cell therapy and blinatumomab."
Leukemia begins in the bone marrow and is spurred by genetic mutations
that cause stem cells in the marrow to produce too many white blood cells, affecting the body's ability to fight infection. Rao and his team had
earlier identified IGF2BP3 as a factor in driving the development of
leukemia -- particularly the MLL-rearranged subtype -- by regulating
various RNA messages that contribute to the disease.

Taking this into account, the researchers wondered whether removing the
IGF2BP3 protein might stop the proliferation of leukemia cells. To answer
the question, Rao and his team used the powerful gene-editing tool known
as CRISPR-Cas9 to remove IGF2BP3 from both MLL-leukemic mice and cell
lines. The effects on survival, they found, were striking.



==========================================================================
Of the leukemic mice that had IGF2BP3 deleted, approximately 75% had an increase in overall survival, and 50% were leukemia-free. The team also observed an average fourfold reduction in the mice's tumor burden --
the total mass of tumor tissue in the body -- after IGF2BP3 removal,
as measured by the weight of their spleens.

"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." In targeting IGF2BP3,
the team also discovered that the protein was not necessary for normal
blood development in mice; the blood system appeared mostly intact when
the protein was removed. Even mice that were completely deficient of
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, who is also a
member of the UCLA Eli and Edythe Broad Center of Regenerative Medicine
and Stem Cell Research.

"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."
While the team studied IGF2BP3 as a target in MLL leukemias, the protein
is also highly expressed in about 15% to 20% of other cancer types,
including glioblastoma, pancreatic cancer, lung cancer and melanoma.

The next step for researchers is to understand whether the removal of
the protein has as strong of an effect against other types of cancer,
as well as to develop small-molecule and RNA-based therapeutics to try
to interfere with the function of the protein.

The work was supported in part by the National Institutes of Health.

========================================================================== Story Source: Materials provided by University_of_California_-_Los_Angeles_Health_Sciences.

Original written by Denise Heady. Note: Content may be edited for style
and length.


========================================================================== Journal Reference:
1. Tiffany M. Tran, Julia Philipp, Jaspal Singh Bassi, Neha Nibber,
Jolene
M. Draper, Tasha L. Lin, Jayanth Kumar Palanichamy, Amit Kumar
Jaiswal, Oscar Silva, May Paing, Jennifer King, Sol Katzman,
Jeremy R. Sanford, Dinesh S. Rao. The RNA-binding protein IGF2BP3
is critical for MLL-AF4- mediated leukemogenesis. Leukemia, 2021;
DOI: 10.1038/s41375-021-01346-7 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/07/210729083434.htm

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