A new mouse genetic study suggests that genomic screening before treatment with certain chemotherapies may help prevent life-threatening anemia. [Ernesto del Aguila III, NHGRI]
A new mouse genetic study suggests that genomic screening before treatment with certain chemotherapies may help prevent life-threatening anemia. [Ernesto del Aguila III, NHGRI]

Genetic mutations that lead to a loss of function (LOF) for a specific enzyme or gain of function (GOF), creating an over-active molecule, are often the underlying cause of various cancers, such as leukemia. Specifically, the loss of the phosphatase and tensin homolog (Pten), which normally keeps cell growth in check, or the over-activation of the SH2-containing tyrosine phosphatase (Shp2) that normally enhance cell proliferation, have been strongly associated with carcinogenesis. Some chemotherapeutic agents have been designed to target Shp2 and other enzymes along the same metabolic signaling pathway.

However now, researchers at University of California, San Diego School of Medicine have discovered that mice lacking both Pten and Shp2 cannot produce and sustain enough red blood cells—shedding insight into why anemia is a common side effect of anti-cancer drugs that target enzymes involved in tumor growth.

“Based on this unexpected finding, we might want to think about screening cancer patients’ genetic backgrounds for loss of Pten or Pten-regulated signals before prescribing anti-cancer drugs that might do more harm than good,” explained senior author Gen-Sheng Feng, Ph.D., professor of pathology at UC San Diego School of Medicine. “In addition, this information could help guide better design of pharmaceuticals for leukemia and other types of cancer in the era of precision medicine.”

The findings from this study were published recently in PNAS through an article entitled “Shp2 and Pten have antagonistic roles in myeloproliferation but cooperate to promote erythropoiesis in mammals.”

Dr. Feng and his team created strains of genetically engineered mice to be deficient in either Pten, Shp2 or both enzymes. The investigators observed that the Pten-deficient mice had elevated white blood cells counts, consistent with leukemia. However, the Shp2-deficient mice were shown to have the opposite symptoms—lower white blood cell counts.

Interestingly, the mice that lacked both Pten and Shp2 had relatively normal white blood cell counts. Yet, researchers were confounded that despite the apparent reversal of leukemia, the mice lacking both enzymes had shorter life spans than normal mice or mice lacking a single enzyme. 

Dr. Feng and his team discovered that the combined deficiency of Shp2 and Pten manifested a lethal anemia and that it was caused by two main factors: red blood cells failed to develop properly from bone marrow, and the red blood cells that did form did not last quite as long as they would normally.

Treating the Pten-deficient mice with a Shp2 inhibitor or the chemotherapeutic agent trametinib, which inhibits a different enzyme along the same signaling pathway as Shp2, led to a positive confirmation of UCSD researcher’s genetic studies.    

“The lethal anemia was caused collectively by skewed progenitor differentiation and shortened erythrocyte lifespan,” the researchers stated. “Consistently, treatment of Pten-deficient mice with a specific Shp2 inhibitor suppressed myeloproliferative neoplasm while causing anemia.”

Trametinib is widely used to treat pancreatic and other types of cancer, and it’s known for frequently causing anemia in patients who receive the drug. Dr. Feng’s team found that trametinib treatment had an effect similar to removing the Shp2 gene or chemical inhibition of Shp2—severely anemic mice.

“What we’ve learned is that even if we know a lot about how individual molecules function in a cell, designing effective therapeutics that target them will require a more comprehensive understanding of the cross-talk between molecules in a particular cell type, and in the context of disease,” concluded Dr. Feng.








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