Investigators at St. Jude Children's Research Hospital discovered the underpinnings of a genomic alteration that occurs in patients with Philadelphia chromosome–like acute lymphoblastic leukemia. The findings will help researchers design clinical trials that combine chemotherapy and targeted therapies, potentially extending survival for these patients.

A new study identifies the underpinnings of a genomic alteration that occurs in children and young adults with a particularly aggressive form of acute lymphoblastic leukemia (ALL), potentially leading to targeted treatment options for those whose tumors progress on standard therapy. The findings will aid in designing clinical trials in which patients with Philadelphia chromosome–like (Ph-like) ALL will receive a combination of chemotherapy and approved drugs.

In previous studies, researchers from St. Jude Children's Research Hospital in Memphis, TN, identified chromosomal rearrangements of the erythropoietin receptor (EPOR) gene in Ph-like ALL, but they did not understand how the rearrangements occurred or how they activated the JAK–STAT signaling pathway in ALL.

In this study, the researchers analyzed 3,115 cases of childhood, adolescent, and young adult B-cell precursor ALL, 212 of which had a gene expression profile of Ph-like ALL (Cancer Cell 2016;29:186–200). Of the latter, 19 had EPOR rearrangements, including those identified in previous research, representing about 9% of their Ph-like ALL cases.

Each EPOR rearrangement results in overexpression of a truncated form of the receptor, which is hypersensitive to erythropoietin, says the study's senior investigator, Charles Mullighan, MD, co-leader of the Hematological Malignancies Program at St. Jude. Erythropoietin then binds to the overexpressed receptors, leading to heightened activation of the JAK–STAT pathway.

The researchers demonstrated that combining the JAK–STAT inhibitor ruxolitinib (Jakafi; Incyte)—currently approved to treat myelofibrosis—with conventional chemotherapy slowed tumor growth in engineered mouse cells and human leukemic cells.

“We found that JAK–STAT inhibitors were active and that they synergized with the chemotherapy drugs that we routinely use now,” including dexamethasone, vincristine, and daunorubicin, Mullighan says. “We saw remarkable and dramatic improvements in tumor cells that were often refractory or partially resistant to active chemotherapy.”

St. Jude is now working with the Children's Oncology Group (COG) to design trials using whole-genome sequencing to detect targetable alterations and guide patients with leukemia into appropriate clinical trials. As part of their research, Mullighan's team developed a diagnostic test using gene expression assays that could be used to screen for EPOR rearrangements.

The findings will help inform research on many Ph-like ALL alterations, which tend to increase with age and are present in about 27% of all patients with ALL between ages 21 and 39, says Lee Greenberger, PhD, chief scientific officer of the Leukemia and Lymphoma Society, based in White Plains, NY. The EPOR rearrangements, which are found in 3% to 4% of Ph-like ALL tumors, are among many chromosomal rearrangements that are targetable by inhibiting the JAK–STAT or other signaling pathways.

“There could be other kinase inhibitors that might work for these patients,” he says. “This paper shows that diagnostic tools for specific rearrangements can be developed and could guide the use of precision therapeutics to treat patients with such genetic alterations.” –Janet Colwell

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©2016 American Association for Cancer Research.
2016
American Association for Cancer Research.