12:12am Monday 26 August 2019

Researchers Sequence Genome of Anaplastic Large Cell Lymphoma, Identify Key Mutations to Target

This image illustrates the effect that mutations in the genes JAK1 and STAT3 have in driving tumor growth in patients with anaplastic lymphoma kinase-negative anaplastic large cell lymphoma. These mutations are especially powerful when both genes are activated. The domino chips represent the genes’ activity along the signaling pathway that, when working together, promote tumor growth. JAK1 inhibitors, represented by the sumo wrestler, can prevent the cascade of falling dominoes, essentially blocking tumor growth.

Image credit: FenicePool

In the study, published April 13 in Cell Press, the team, led by Dr. Giorgio Inghirami of Weill Cornell Medical College and Dr. Raul Rabadan of Columbia University College of Physicians and Surgeons, sequenced the genomes of tumor tissue from 88 different patients with anaplastic lymphoma kinase-negative large cell lymphoma (ALCL). ALCL is a common form of T-cell lymphoma, which accounts for about 15 percent of all non-Hodgkin lymphomas in the United States.

Massive sequencing data revealed that more than 38 percent of the tumors contained mutations in two genes, called JAK1 and STAT3. The researchers then examined the results when the genes were left intact and when they were blocked in cell cultures and in animals. They found that there was significantly less tumor growth when JAK1 and STAT3 were inhibited. JAK1 and STAT3 happen to reside along the same pathway, making them increasingly powerful to perpetuate harmful phenotypes once they are created. Dr. Inghirami likens this concept to a car (the cancerous cell) being propelled by gasoline (the mutations along a pathway that enable communication to continue).

“Since you have two defects, you are pushing the gas much more powerfully than when you push once,” said Dr. Inghirami, the article’s senior author and a professor of pathology and laboratory medicine at Weill Cornell Medical College.

This makes the mutations especially harmful, but they also offer a more concentrated mark to target therapeutically, Dr. Inghirami said. While there isn’t an effective STAT3 inhibitor currently, the mutation’s activity is contingent upon JAK1. There are, however, JAK1-inhibiting drugs, which could silence JAK1 while also inhibiting STAT3’s activity, effectively curbing this previously untreatable mutation.

Mutations in the JAK1 gene have been implicated in other diseases such as blood disorders and abnormal liver growths, and investigators have successfully developed inhibitors that are approved by the U.S. Food and Drug Administration for those conditions. Investigators are currently working to have other existing inhibitors approved to treat ALCL, and are also developing new JAK1 inhibitors that may have fewer side effects.

“Now we have a class of drugs that will potentially work in this population,” Dr. Inghirami said. “The interesting part is that pathway is now being found in different diseases – it looks like a recurring motif. So maybe we have the capacity to expand the therapeutic efficacy of this drug to others with similar phenotypes.”

Weill Cornell Medical College.

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