A child stricken with leukemia is a heartbreaking situation, and the search for improved treatments is ongoing. Now, UCLA researchers have discovered how a cellular protein contributes to an aggressive form of leukemia common in young children. They note that the finding is an important step forward in the struggle to better understand and treat aggressive childhood leukemia. The research was published on March 14 in the Journal of Clinical Investigation.
“Certain subtypes of leukemia are very hard to treat and typically children with these subtypes have poor prognosis,” explained senior author Dinesh Rao, MD, PhD, a member of the UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research. He added, “Pinpointing specific differences in how cancer cells function is critical in the development of targeted treatments, especially for these types of aggressive cancers that often recur and don’t respond well to standard treatments like chemotherapy.”
Leukemia is a blood cancer; the bone marrow contains the stem cells that develop into all types of mature blood cell. In leukemia, genetic mutations cause abnormal multiplication of white blood cells; thus, affecting the body’s immune system and inhibiting its ability to fight infection. The most common childhood cancer is B-acute lymphoblastic leukemia (B-ALL). It is a fast-growing malignancy that starts in white blood cells called B cells. It is often successfully treated with chemotherapy; however, genetic mutations in a gene called mixed lineage leukemia (MLL) result in an aggressive subtype of B-ALL known as MLL-rearranged; this is the most common type of acute lymphoblastic leukemia in infants. This subtype is much more difficult to treat; it often recurs, and survival rates are poor.
The UCLA investigators focused their research on the difference between MLL-rearranged and other forms of leukemia. They began by analyzing bone marrow samples from children with B-ALL and cataloging every protein present in the leukemia cells. Then, they focused on which proteins were more predominant in the MLL-rearranged subtype. A specific protein called IGF2BP3 stood out because of its extensive presence in the cells and its ability to bind to RNA messages within the cell.
RNA messages are copies of small sections of DNA that move out of the cell nucleus to be converted into proteins. Certain proteins cause cells to grow and divide when needed. Too little or too much production of these critical proteins can cause disease. Researchers are aware that the IGF2BP3 protein is present in cancerous cells and tumors; however, the protein’s function was unknown until now. Dr. Rao and his team found that it plays an important role in the development of the MLL-rearranged subtype of leukemia by regulating various RNA messages that contribute to the disease.
The researchers collaborated with coauthor Jeremy Sanford of UC Santa Cruz, the team examined the role IGF2BP3 played within the leukemia cells. They found that IGF2BP3 binds to and stabilizes hundreds of leukemia-promoting RNA messages and consequently increases how much protein is made, resulting in an environment that is favorable to leukemia cell growth. The investigators then added IGF2BP3 to mouse bone marrow. This caused atypical growth of blood-forming stem cells that were more likely to produce the abnormal B cells most common in B-ALL. These abnormal blood cells were found to have increased levels of the leukemia-promoting RNA messages, which is why they were able to grow more quickly. The researchers also found that removing the IGF2BP3 protein from leukemia cells resulted in decreases in leukemia-promoting messages, which in turn killed the leukemia cells.
“Our findings tell me that IGF2BP3’s role in aggressive leukemia is quite significant,” noted Dr. Rao. He added, “Further research is needed to characterize how we can potentially remove or block this protein to stop the proliferation of leukemia cells.” The next phase in the research will be to determine whether the IGF2BP3 protein plays a role in other types of leukemia, and testing drugs or compounds that might inhibit the protein and effectively kill leukemia cells in patients.