Mutant Genes in High-Risk Childhood Leukemias Identified

/PRNewswire / -- A research team has pinpointed a new class of gene mutations, which identify cases of childhood acute lymphoblastic leukemia (ALL) that have a high risk of relapse and death. The finding suggests specific drugs that could treat this high-risk leukemia subtype in children, particularly because such drugs are already in clinical trials for similar blood diseases in adults.

While the cure rate in pediatric ALL has reached about 85 percent, the remaining high-risk cases have proven especially intractable because they arise from different, unidentified genetic mutations.

Discovery of the mutations was led by scientists from St. Jude Children's Research Hospital, the Children's Oncology Group (COG), the University of New Mexico Cancer Research and Treatment Center, Albuquerque, N.M., and the National Cancer Institute (NCI), part of the National Institutes of Health (NIH). This research was done as part of the NCI Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative, which seeks to utilize the study of genomics to identify therapeutic targets in order to develop more effective treatments for childhood cancers. The article appears online May 18 in the early edition of the Proceedings of the National Academy of Sciences.

"We have made such great progress in curing children with ALL that the main challenge is now the remaining high-risk patients," said St. Jude Scientific Director, James Downing, M.D., a co-senior author of the study. "We still do not know how to accurately identify these patients and effectively treat them to provide the highest chance for a cure. The problem is that this high-risk group is likely a heterogeneous mixture of biologic subtypes."

The new study builds on the researchers' previous genetic analysis of the leukemic cells from pediatric ALL patients.

"The findings from our previous studies have 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," said Charles Mullighan, M.D., Ph.D., assistant member in the St. Jude Department of Pathology and a co-first author of the study. "Such mutations would cause those kinases to be stuck in the on position, triggering the uncontrolled proliferation of white blood cells that is seen in leukemia."

Thus, 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 leukemic cells from 187 patients with high-risk ALL. That analysis revealed mutations in about 10 percent of the cases in a family of protein kinases called JAK, whose members were also known to be mutated in other types of leukemias 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 Stephen Hunger, M.D., chairman of the COG ALL committee and a co-senior author of the study. "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."

The researchers discovered, in some high-risk ALL patients, that mutations in JAK appeared to work in concert with another mutation -- in the gene IKZF1 -- which they had earlier found to underlie such cases.

"Our studies of these leukemia subtypes indicate that leukemia is not necessarily a single-cause disease," said Cheryl Willman, M.D., director and CEO of the University of New Mexico Cancer Research and Treatment Center and a co-senior author of the study. "A patient may have multiple different genetic lesions that target different cellular pathways to induce leukemia. Thus, it is very important to develop new therapies that target these specific mutations, and our discovery of JAK as target now allows us to begin to develop clinical trials with JAK inhibitors for children and adults with this form of disease."

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.

The discovery that mutations in JAK underlie some cases of high-risk ALL is enough to warrant clinical trials of inhibitory drugs to treat such cancers.

"JAK-inhibiting drugs are now moving into clinical trials for treatment of such adult myeloproliferative diseases as polycthemia vera, essential thrombocytosis and primary myelofibrosis," Downing said. "We expect that there will soon be initial clinical studies to assess the safety and effectiveness of these drugs in children with relapsed ALL in which JAK mutations have been identified within their leukemic cells."

Such studies would be coordinated by the COG, an international clinical trial cooperative group supported by the NCI.

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; CureSearch; St. Baldrick's Foundation; a National Health and Medical Research Council (Australia) CJ Martin Traveling Fellowship; and ALSAC.

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Smothered Genes Combine with Mutations to Yield Poor Outcome

Johns Hopkins Kimmel Cancer Center researchers have identified a set of genes in breast and colon cancers with a deadly combination of traditional mutations and “smothered” gene activity that may result in poor outcomes for patients.

The Hopkins team showed that this smothering process, called epigenetic inactivation, contributes to the aggressiveness of breast and colon cancer by disrupting biochemical pathways that normally suppress the runaway growth of cells that is the hallmark of cancer. While mutations alter pathways by rewriting the gene’s DNA code, epigenetic marks affect genes without changing the code itself.

“Until studies like ours, it was easy to think that if we didn’t find gene mutations in certain biochemical pathways linked to breast or colon cancer, then those pathways were normal in such patients,” says Stephen Baylin, M.D., the Virginia and D.K. Ludwig Professor for Cancer Research and deputy director of the Kimmel Cancer Center. “Now we know that, in some patients, the pathways involved with newly discovered mutated genes are often more frequently disrupted by epigenetic mechanisms rather than genetic ones.”

“That’s a powerful insight that could help us diagnose patients quicker, predict the course of their cancer more accurately and in the future treat the disease more effectively,” adds Baylin. A report on this work appeared May 27 in PLoS Medicine.

The team made their discovery using microarray technology – special silicon chips carrying pieces of genetic material that allow thousands of genes to be analyzed at one time. For this study, microarrays were tailored to locate cancer-related genes inactivated by an epigenetic process called DNA methylation. This methylation involves the binding of molecules called methyl groups to elements of DNA called cytosines that are located in a gene’s “on-off switch.” Excess methylation smothers the gene with too many methyl groups and interferes with the gene’s normal protein production, setting the stage for a lethal cancer.

Some 189 mutated genes in breast and colon cancers, previously identified by a Kimmel Cancer Center research team, were screened for methylation by Baylin’s group. They found 36 genes that were infrequently mutated in cancer, but were “hyper”methylated, often in both breast and colon cancers. After reviewing samples from 30 breast and 20 colorectal cancer patients as well as information from public microarray databases, the researchers found 18 of these genes that were strongly linked to poor outcome of patients with tumors carrying these changes.

For most of the genes, the researchers were able to reverse their epigenetic change and reactivate them in test tubes by stripping off excess methyl groups. This suggests that new treatments designed to reverse hypermethylation could be a simpler and more practical approach to treating cancer than strategies that attempt to replace, deactivate or compensate for mutated genes, according to Baylin.

Baylin also believes that the methlylated genes identified in this study could be inactivated in a broader range of cancers as well. That means the current findings could be extended to other cancers, improving the ability of physicians to predict the course of additional types of tumors, he says.

“We’ve learned from this study that we must include both genetic and epigenetic changes when we do future microarray analyses to increase our understanding of the genetic basis of cancer,” Baylin says. “Such information will provide new details about why cancers start and help us identify which cancers will be particularly aggressive in our patients.”

Participants in the study included Timothy Chan, Sabine Glockner, Joo Mi Yi, Wei Chen, Leslie Cope, James Herman, Victor Velculescu, Kornel Schuebel, and Nita Ahuja of Johns Hopkins, and Leander Van Neste of Ghent University, Belgium.

This work was supported by the National Institute of Environmental Health Sciences and the National Cancer Institute.