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Genomic Study Yields Gene That Helps Predict Leukemia Relapse

NEW YORK (GenomeWeb News) – New research appearing online last night in the New England Journal of Medicine has uncovered a key gene for predicting treatment failure and relapse in acute lymphoblastic leukemia, a type of childhood leukemia.
 
A team of American researchers did genetic profiling of more than 200 children with high-risk acute lymphoblastic leukemia to identify genetic changes associated with poor outcomes. Along with the more than 50 copy number alterations they detected, the team found significant and reproducible associations between mutations or deletions in a gene called IKZF1 and poor ALL outcomes.
 
These mutations, in turn, appear to be linked to a stem-cell like gene expression signature — a finding that researchers say provides a new look at ALL biology. In addition, the results suggest IKZF1 status may eventually be used to help distinguish patients who will respond well to current therapies from those who won’t.
 
“The findings of this study help us further subdivide those patients who are unlikely to be cured, and identify patients in whom different therapies should be tested,” co-author Stephen Hunger, University of Denver researcher and chairman of the Children’s Oncology Group ALL committee, said in a statement.
 
Acute lymphoblastic leukemia is a cancer of white blood cells called lymphocytes, including B-cells and T-cells, which affects roughly one in every 29,000 children. Existing ALL therapies are successful about 80 percent of the time. But side effects are harsh and up to a fifth of ALL patients eventually relapse. For children who do relapse, the five-year survival rate is just 30 percent.
 
In an effort to identify molecular risk factors for predicting which patients will respond best to existing treatments, the researchers did genetic profiling of children with high-risk leukemia to identify genetic changes and then examine which of these, if any, were associated with ALL outcomes.
 
The work was done as a pilot project within the NCI’s Therapeutically Applicable Research to Generate Effective Treatments, or TARGET, project — a National Cancer Institute-funded initiative aimed at using genomics to find new treatments and improve treatment response for childhood cancers.
 
The researchers genotyped samples from 221 children with a high-risk form of ALL called B-cell progenitor ALL using Affymetrix microarrays. They then looked for patterns related to ALL outcomes in the group, using follow-up data acquired over a median of nearly four years.
 
Because the patients were known to have a high-risk form of ALL, lead author Charles Mullighan, a pathologist at St. Jude Children’s Research Hospital in Memphis, told GenomeWeb Daily News, they received particularly intensive and rigorous ALL treatment.
 
The team identified 50 recurring copy number abnormalities — many in genes involved in B-cell regulation and development. Using principal component analysis, the researchers found a significant association between the expression or copy number status of 20 genes and treatment outcome.
 
In the original cohort, for instance, those in the high-risk group had a 75 percent incidence of adverse events and a 73.8 percent incidence of relapse over five years. Those in the low risk group had a 27 percent incidence of adverse events and 25 percent relapse in the same time frame.
 
In a validation cohort involving another 258 children with either standard or high-risk (B-cell progenitor) ALL, those in the high-risk group had a 56.9 percent incidence of adverse events and a 47 percent incidence of relapse over a decade compared to a 26.8 percent incidence of events and 24.6 percent incidence of relapse in the low-risk group.
 
Next, the team looked at the effects of each gene in this signature. They found what appears to be an independent association between mutations in a gene called IKZF1 and poor ALL outcomes in both the original and validation cohorts. That was reassuring, since the validation group included different ALL subtypes, with children receiving different treatments than those in the original group, researchers noted.
 
IKZF1 codes for a transcription factor called IKAROS that contributes to the lymphocyte formation and B- and T-cell function. The biological role of the protein is not well understood, though mutations in IKZF1 have been previously linked to ALL and other blood cancers.
 
And IKZF1 alterations appear to be widespread. Nearly a third of patients tested carried IKZF1 deletions. For example, in the original group of 211 patients, the team detected complete IKZF1 deletions in 16 patients and partial deletions in or upstream of the gene’s coding region in another 47 patients.
 
In addition, leukemia cells from patients who carried IKZF1 mutations had gene expression profiles similar to hematopoietic stem cells and progenitor cells but had dialed back expression of genes involved in B lymphoid cell function. Based on these and other results, the team speculated that IKZF1 mutations might trigger a developmental arrest hindering B-cell maturation and contributing to chemotherapy resistance.
 
That raises the possibility that IKZF1 status could eventually be used prognostically to predict treatment outcomes. But before that happens, the current research needs to be validated by independent research groups — an effort that is already underway, senior author James Downing, St. Jude scientific director, told GenomeWeb Daily News. Downing also noted that finding the best way to assess IKZF1 in the clinic may be complicated by the fact that a range of IKZF1 mutations are associated with ALL.
 
In terms of developing new treatments targeting the mutations, Downing cautioned that researchers don’t know enough about IKAROS biology to make that feasible at this point. But, he explained, the gene is a promising prognostic marker and opens up new avenues to pursue in terms of ALL biology.
 
Data from the TARGET program is being made publicly available here. Co-author Daniela Gerhard, director of NCI’s Office of Cancer Genomics, told GenomeWeb Daily News that a data-request process will be put in place to protect data that could potentially identify patients. That aspect of the data portal is currently under construction, Gerhard said.
 

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