Working with other doctors and institutions, a University of Colorado Denver School of Medicine faculty member has helped identify a genetic mutation that, if controlled, might save the lives of some children suffering from the country’s most common type of childhood cancer – acute lymphoblastic leukemia or ALL.
Mutations in Janus kinases or JAK proteins strongly predict whether children being treated for ALL will relapse, said Stephen Hunger, MD, Professor of Pediatrics, Ergen Family Chair in Pediatric Cancer and Chief of the Section of Pediatric Hematology/Oncology at The Children’s Hospital in Denver. Janus kinases are enzymes that control the growth of white blood cells, which grow out of control in people with leukemia. Fortunately, Hunger said, there are drugs directed at these JAK mutations that are currently being tested in adult blood diseases. “We hope that these drugs could help kids with ALL and JAK mutations,” he said.
Hunger, in his role as a leader of the international Children’s Oncology Group, is a co-senior investigator of the JAK study.
Scientists from the Children’s Oncology Group, St. Jude Children’s Research Hospital, Memphis, Tenn., the University of New Mexico Cancer Research and Treatment Center, Albuquerque, N.M., and the National Cancer Institute (NCI) played major roles in the study, which appeared Monday in the journal Proceedings of the National Academy of Sciences.
Despite high cure rates, acute lymphoblastic leukemia ranks as the second leading cause of cancer death in children. For children with ALL treated in a Children’s Oncology Group study, those with mutations in JAK proteins had a much higher chance of relapse, the study reports. So stopping JAK mutations becomes critical to stopping the progression of this subtype of ALL, which is fatal to seven in 10 children who relapse.
The new study builds on the researchers’ previous genetic analysis of high-risk ALL patients’ abnormal white blood cells. That first analysis showed a high frequency of changes in a gene called IKAROS among kids who relapsed during treatment for acute lymphoblastic leukemia. The latest study shows that JAK mutations and IKAROS genes are closely linked. This discovery, according to Hunger, provides a clear roadmap on the steps needed to use new therapies directed against JAK mutations in this subtype of ALL.
Charles Mullighan, MD, PhD, assistant member in St. Jude Pathology and a co-first author of the JAK study, agreed: “The findings from that [IKAROS] analysis hinted that some high-risk ALL cases might arise from mutations in genes that produce enzymes called kinases, which function as biological on-off switches in cells. Such mutations would cause those kinases to be stuck in the on position, triggering the uncontrolled proliferation of white blood cells seen in leukemia.”
The researchers began to analyze the genetic sequences of many kinases known to be components of the proliferation machinery of white blood cells. The team analyzed the blood cells from 187 young patients with high-risk ALL. That analysis revealed mutations in about 10 percent of the cases in the Janus kinase, whose members were also known to be mutated in other types of leukemia and related diseases.
“Further studies of these mutant JAK proteins revealed that the changes in their molecular structures could switch them on to drive the blood cell proliferation that is characteristic of ALL,” said Hunger. “What’s more, in test tube studies, we found that drugs blocking the activation of the mutant JAK kinases prevented uncontrolled growth suggesting that drugs that target JAK proteins might be effective in this subtype of ALL.”
“Our studies of these leukemia subtypes indicate that leukemia is not necessarily a single-cause disease,” said Cheryl Willman, MD, director and CEO of the University of New Mexico Cancer Research and Treatment Center and with Hunger a co-senior author of the study. “A patient may have multiple different genetic lesions that target different cellular pathways to induce leukemia.”
In further studies, the researchers plan to identify mutations in kinase genes and other enzymes that underlie high-risk ALL, as well as explore how these abnormalities might work together to drive the cancers.
Such studies would be coordinated by the Children’s Oncology Group, an international clinical trial cooperative group supported by the National Cancer Institute.
Other authors of the paper are Racquel Collins-Underwood, Letha A. Phillips, Xiaoping Su, Wei Liu and Brenda Schulman (St. Jude); Sarah Tasian and Mignon Loh (University of California San Francisco); Meenakshi Devidas (Children’s Oncology Group); Susan Atlas, I-Ming Chen and Richard C. Harvey (University of New Mexico Cancer Research and Treatment Center, Albuquerque); Robert J. Clifford, Daniela Gerhard, Malcolm Smith and Jinghui Zhang (National Cancer Institute); William Carroll (New York University Cancer Institute); and Gregory H. Reaman (The George Washington University).
This research was supported in part by a supplement to the Children’s Oncology Group Chair’s award; a National Cancer Institute Strategic Partnering to Evaluate Cancer Signatures Program award; the National Institutes of Health/National Institute of General Medical Sciences Pharmacogenetics Research Network and Database; National Institutes of Health Cancer Center Core Grants; the Children’s Oncology Group and Statistical Center; the Leukemia and Lymphoma Society Specialized Center of Research grant supporting University of New Mexico Cancer Center Shared Resources; CureSearch; St. Baldrick’s Foundation; a National Health and Medical Research Council (Australia) CJ Martin Traveling Fellowship; and ALSAC.
The School of Medicine faculty work to advance science and improve care as the physicians, educators and scientists at University of Colorado Hospital, The Children’s Hospital, Denver Health, National Jewish Health, and the Denver Veterans Affairs Medical Center. Degrees offered by the CU Denver School of Medicine include doctor of medicine, doctor of physical therapy, and masters of physician assistant studies. The School is part of the University of Colorado Denver, one of three campuses in the University of Colorado system. For additional news and information, please visit the CU Denver newsroom online.
St. Jude Children’s Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fundraising organization. For more information, please visit www.stjude.org.
Children’s Oncology Group (COG), the world’s largest cooperative pediatric cancer research organization, which includes every recognized pediatric cancer program in North America, comprises a network of more than 5,000 physician, nurse, and other clinical and laboratory investigators whose collaboration in clinical and translational research has turned childhood cancer from a virtually incurable disease to one with an overall cure rate approaching 80 percent. COG is committed to conquering childhood cancer through scientific discovery and compassionate care. For more information, please visit www.childrensoncologygroup.org.
The University of New Mexico Cancer Research and Treatment Center is New Mexico’s only National Cancer Institute-designated cancer center, and is home to the state’s largest and most experienced team of cancer experts with 81 board-certified oncology physicians and more than 120 research scientists, supported by more than $50 million in grants annually. As the Official Cancer Center of the State of New Mexico, the Center served 7,600 new patients last year in 84,000 patient visits, treating nearly half of all adults with cancer in the state and virtually all the children.
The National Cancer Institute leads the National Cancer Program and the NIH effort to dramatically reduce the burden of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI Web site at http://www.cancer.gov or call NCI’s Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).