Although therapies for acute lymphoblastic leukemia have been effective, there are still a significant amount of cases that relapse and develop short- and long-term effects.  A new mouse study demonstrates that changes in a protein called IL-7R are sufficient to initiate a type of leukemia. The new findings open up a door to understanding the molecular players involved in the onset of leukemia and may lead to the development of better and targeted treatments.

The findings are published in the journal Nature Communications in a paper titled, “IL7R mutational activation can initiate precursor B-cell acute lymphoblastic leukemia.”

“Interleukin-7 receptor α (encoded by IL7R) is essential for lymphoid development,” the researchers wrote. “Whether acute lymphoblastic leukemia (ALL)-related IL7R gain-of-function mutations can trigger leukemogenesis remains unclear. Here, we demonstrate that lymphoid-restricted mutant IL7R, expressed at physiological levels in conditional knock-in mice, establishes a pre-leukemic stage in which B-cell precursors display self-renewal ability, initiating leukemia resembling PAX5 P80R or Ph-like human B-ALL.”

ALL starts in the bone marrow. Most often, the leukemia cells invade the blood fairly quickly. They can also sometimes spread to other parts of the body. Although therapies for ALL are highly effective, with five-year survival rates reaching 80–90%, a significant number of ALL cases still relapse and the use of intensive chemotherapy has short- and long-term side effects.

The researchers used mouse models and discovered that mutations in IL-7R that lead to the constant activation of this protein are sufficient to trigger the disease.

“The exact same mutations are found in human patients and so we believe that these changes in IL-7R can be at the origin of the disease also in people,” explained João T. Barata, coordinator of the study.

“It’s important to find new therapeutic strategies to improve the efficacy of the current treatments and to reduce the probability of secondary effects. The mice we generated develop leukemia with very similar characteristics to that found in humans. These mice can be used to identify and test new treatments, such as drugs that decrease the activation of IL-7R, including some that we discovered in this work,” said Afonso Almeida, first author of the study.

The researchers previously demonstrated that the importance of the high levels of IL-7R for the development of acute lymphoblastic leukemia. In the current study, they were able to show that mutations that increase the function of the protein IL-7R, even without increasing its normal levels, are sufficient to trigger the disease. “The two studies complement each other in showing different aspects of the ability of IL-7R to originate leukemia and in demonstrating that drugs that inhibit the molecular effects of IL-7R may constitute valid therapeutic options for patients sometime in the future,” added Barata.

“In summary, we generated an in vivo model that formally demonstrates that IL7R gain-of-function drives bona fide precursor B-ALL and, importantly, can initiate the disease. Our model constitutes a resource to characterize new molecular and cellular players in B-ALL etiology, in the context of otherwise normal hematopoietic development, and to test new therapeutic approaches in an immunocompetent setting,” concluded the researchers.

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