Scientists have identified mutations in a gene that predict a high likelihood of relapse in children with acute lymphoblastic leukemia (ALL). Although the researchers caution that further research is needed to determine how changes in the gene, called IKZF1 or IKAROS, lead to leukemia relapse, the findings are likely to provide the basis for future diagnostic tests to assess the risk of treatment failure. By using a molecular test to identify this genetic marker in ALL patients, physicians should be better able to assign patients to appropriate therapies. The findings of the Children Oncology Group (COG) study, led by scientists from St. Jude Children Research Hospital, Memphis, Tenn., 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, appear online Jan. 7, 2009, in the New England Journal of Medicine, and in print on Jan. 29, 2009. ALL, a cancer of white blood cells, is the most common childhood cancer, in that it is diagnosed in about one in 29,000 children annually. Using currently available therapies, cure rates for ALL are now upwards of 80 percent. However, those therapies carry with them substantial side effects, and even with treatment, only 30 percent of children who experience a relapse of ALL will survive five years. Determining the risk of relapse faced by an individual patient would help physicians tailor treatment intensity appropriately, but until now there has been no good marker for predicting outcome. "Great progress has been made in recent years in improving the cure rate of childhood ALL," said Stephen Hunger, M.D., chairman of the COG ALL committee and the lead COG investigator on this study. "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." In the study, researchers analyzed genetic data on leukemia cells obtained at diagnosis from 221 children with high-risk leukemia (i.e., a high chance of relapse) who had been treated in an existing COG study. They conducted their analysis using microarrays and DNA sequencing � technologies which allow researchers to quickly and efficiently identify and analyze multiple genes simultaneously in the same cell. Using these technologies to identify genetic abnormalities in leukemia cells, the investigators examined the DNA of the leukemia cells at the time of diagnosis and then determined if any of the identified genetic changes predicted relapse. To confirm that specific genetic changes were associated with relapse, the scientists also examined a second group of 258 children with ALL who were treated at St. Jude. "We looked across the genome in an unbiased fashion in an attempt to pull out any genes that were significantly associated with outcome," said Charles Mullighan, M.D., Ph.D., assistant member in the St. Jude Department of Pathology and the paper抯 first author. "From these findings, we identified a group of genetic abnormalities that together predicted poor outcome." The most significant association was with the deletions or changes in the IKAROS gene. Mutations of IKAROS were shown to identify a subgroup of patients who were treated in the COG study that had a very poor prognosis. The prognostic significance of these genetic alterations was validated in the independent St. Jude patient group, a finding of particular importance since different types of therapies were used in these two groups of patients. Previous research has shown that the IKAROS gene serves as the blueprint for production of the IKAROS protein, which regulates the activity of many other genes. The IKAROS protein plays an essential role in the development of lymphocytes, the white blood cells that, when changed, give rise to pediatric ALL. The way in which IKAROS abnormalities contribute to the development of relapse remains to be determined. The study also examined gene expression in the leukemia cells using microarray chips, and found that leukemia cells from patients with IKAROS alterations expressed primitive, stem cell-like genes, suggesting that the cells are less mature and possibly more resistant to the effects of drugs used to treat ALL. "These findings show how detailed analysis of leukemic cells using complementary techniques can enhance our understanding of the genetic basis of leukemia," said co-author Cheryl Willman, M.D., director and CEO, University of New Mexico Cancer Research and Treatment Center. The researchers also tested whether the presence of IKAROS alterations was associated with levels of minimal residual disease, another measure of treatment response in ALL. "Measurement of levels of minimal residual disease is widely used to monitor treatment responsiveness and also to alter patients� therapy if they have a very poor response to treatment," said James Downing, M.D., St. Jude scientific director and the paper抯 senior author. "An important analysis we conducted was to see whether identifying the association of IKAROS alterations with poor outcome added anything to just measuring levels of minimal residual disease. And, indeed, it did." The researchers� analysis indicated that identifying IKAROS alterations may be clinically useful and will complement existing diagnostic tests and measurement of minimal residual disease levels. While a clinical test for alterations of IKAROS could prove valuable for predicting poor outcomes in children with ALL, complexities remain. There are different types of deletions in the gene, some that involve the entire IKAROS gene and others that involve only parts of the gene. Because the genetic alterations in IKAROS in ALL are not uniform or limited to a single mutation or deletion, it may be necessary to develop a panel of different tests to detect IKAROS lesions and identify which patients are at highest risk for relapse. 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 first two cancers being studied in the program are ALL and neuroblastoma, a cancer that arises in immature nerve cells and affects mostly infants and children. Combined, these two cancers account for 3,000 new cases each year, and in both cancers, there are some children who have a very favorable prognosis and others who are at high risk for treatment failure. By determining the genetic factors that distinguish these groups, the hope is that researchers can use this information to improve patient outcomes and develop better treatments, particularly for those in the high-risk group. "In the long term, our goal is to develop effective therapeutic interventions, directed toward vulnerabilities that leukemia cells acquire as a result of the genomic abnormalities identified through the TARGET initiative," said Malcolm Smith, M.D., Ph.D., of NCI抯 Cancer Therapy Evaluation Program. These are the first results to come out of this initiative. For more information about TARGET, please visithttp://target.cancer.gov St. Jude Children's Research Hospital The Children抯 Oncology Group/CureSearch The University of New Mexico Cancer Research and Treatment Center The National Cancer Institute NCI 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). The National Institutes of Health The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
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. For more information, please visit www.stjude.org.
Children抯 Oncology Group (COG), the world抯 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 UNM Cancer Center is New Mexico抯 only National Cancer Institute-designated cancer center, and is home to the state抯 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.
Reference: Mullighan CG, Su X, Zhang J, Radtke I, Phillips LAA, Miller CB, Ma J, Liu W, Cheng C, Schulman BA, Harvey RC, Chen I, Clifford RJ, Carroll WL, Reaman G, Bowman WP, Devidas M, Gerhard DS, Yang W, Relling MV, Shurtleff SA, Campana D, Borowitz MJ, Pui C, Smith M, Hunger SP, Willman CL, Downing JR, and the Children's Oncology Group. Deletion of IKZF1 and Prognosis in Acute Lymphoblastic Leukemia. NEJM. Vol. 360, No.
May 6, 2010
Gene Abnormality Found To Predict Childhood Leukemia Relapse
DNA&RNA Databases and Tools
Databases
Database that groups biomedical literature, small molecules, and sequence data in terms of biological relationships.
Database of Expressed Sequence Tags (dbEST)
A divison of GenBank that contains short single-pass reads of cDNA (transcript) sequences. dbEST can be searched directly through the Nucleotide EST Database.
Database of Genome Survey Sequences (dbGSS)
A division of GenBank that contains short single-pass reads of genomic DNA. dbGSS can be searched directly through the Nucleotide GSS Database.
The NIH genetic sequence database, an annotated collection of all publicly available DNA sequences. GenBank is part of the International Nucleotide Sequence Database Collaboration, which comprises the DNA DataBank of Japan (DDBJ), the European Molecular Biology Laboratory (EMBL), and GenBank at NCBI. These three organizations exchange data on a daily basis. GenBank consists of several divisions, most of which can be accessed through the Nucleotide database. The exceptions are the EST and GSS divisions, which are accessed through the Nucleotide EST and Nucleotide GSS databases, respectively.
A database of static NCBI web pages, documentation, and online tools. These pages include such content as specialized online sequence analysis tools, back issues of newsletters, legacy resource description pages, sample code, and other miscellaneous resources. Searching this database is equivalent to a site search tool for the whole NCBI web site. FTP site is not covered.
A collection of nucleotide sequences from several sources, including GenBank, RefSeq, the Third Party Annotation (TPA) database, and PDB. Searching the Nucleotide Database will yield available results from each of its component databases.
Database of related DNA sequences that originate from comparative studies: phylogenetic, population, environmental and, to a lesser degree, mutational. Each record in the database is a set of DNA sequences. For example, a population set provides information on genetic variation within an organism, while a phylogenetic set may contain sequences, and their alignment, of a single gene obtained from several related organisms.
A public registry of nucleic acid reagents designed for use in a wide variety of biomedical research applications, together with information on reagent distributors, probe effectiveness, and computed sequence similarities.
A collection of curated, non-redundant genomic DNA, transcript (RNA), and protein sequences produced by NCBI. RefSeqs provide a stable reference for genome annotation, gene identification and characterization, mutation and polymorphism analysis, expression studies, and comparative analyses. The RefSeq collection is accessed through the Nucleotide and Protein databases.
The Sequence Read Archive (SRA) stores sequencing data from the next generation of sequencing platforms including Roche 454 GS System®, Illumina Genome Analyzer®, Life Technologies AB SOLiD System® , Helicos Biosciences Heliscope®, Complete Genomics®, and Pacific Biosciences SMRT®
Third Party Annotation (TPA) Database
A database that contains sequences built from the existing primary sequence data in GenBank. The sequences and corresponding annotations are experimentally supported and have been published in a peer-reviewed scientific journal. TPA records are retrieved through the Nucleotide Database.
A repository of DNA sequence chromatograms (traces), base calls, and quality estimates for single-pass reads from various large-scale sequencing projects.
Tools
Allows you to retrieve records from many Entrez databases by uploading a file of GI or accession numbers from the Nucleotide or Protein databases, or a file of unique identifiers from other Entrez databases. Search results can be saved in various formats directly to a local file on your computer.
BLAST (Basic Local Alignment Search Tool)
Finds regions of local similarity between biological sequences. The program compares nucleotide or protein sequences to sequence databases and calculates the statistical significance of matches. BLAST can be used to infer functional and evolutionary relationships between sequences as well as to help identify members of gene families.
Tools that provide access to data within NCBI's Entrez system outside of the regular web query interface. They provide a method of automating Entrez tasks within software applications. Each utility performs a specialized retrieval task, and can be used simply by writing a specially formatted URL.
An integrated application for viewing and analyzing sequence data. With Genome Workbench, you can view data in publically available sequence databases at NCBI, and mix these data with your own data.
Presents data from the NIAID Influenza Genome Sequencing Project and from GenBank, and provides tools for flu sequence analysis, annotation and submission to GenBank. It also provides links to other flu sequence resources, and publications and general information about flu viruses.
A system for quickly identifying segments of a nucleic acid sequence that may be of vector origin. VecScreen searches a query sequence for segments that match any sequence in a specialized non-redundant vector database (UniVec).
Downloads
BLAST executables for local use are provided for Solaris, LINUX, Windows, and MacOSX systems. See the README file in the ftp directory for more information. Pre-formatted databases for BLAST nucleotide, protein, and translated searches also are available for downloading under the db subdirectory.
This site contains files for all sequence records in GenBank in the default flat file format. The files are organized by GenBank division, and the full contents are described in the README.genbank file.
This site contains all nucleotide and protein sequence records in the Reference Sequence (RefSeq) collection. The "release" directory contains the most current release of the complete collection, while data for selected organisms (such as human, mouse and rat) are available in separate directories. Data are available in FASTA and flat file formats. See the README file for details.
This site contains the UniVec and UniVec_Core databases in FASTA format. See the README.uv file for details.
Submissions
A web-based sequence submission tool for one or a few submissions, designed to make the submission process quick and easy.
Tool to submit Barcodes, short nucleotide sequences from a standard genetic locus for use in species identification.
A stand-alone software tool developed by the NCBI for submitting and updating entries to public sequence databases (GenBank, EMBL, or DDBJ). It is capable of handling simple submissions that contain a single short mRNA sequence, complex submissions containing long sequences, multiple annotations, segmented sets of DNA, as well as sequences from phylogenetic and population studies with alignments. For simple submission, use the online submission tool BankIt instead.
A command-line program that automates the creation of sequence records for submission to GenBank using many of the same functions as Sequin. It is used primarily for submission of complete genomes and large batches of sequences.
May 5, 2010
Xinjiang discovery provides intriguing DNA link
CHANGCHUN, April 29 (Xinhua) -- The DNA of some 4,000 year-old bodies unearthed five years ago in Xinjiang, in northwest China, provides scientific evidence of early intermingling between people of European and Asian origin.
Zhou Hui, a professor of life science and her team discovered that some of the earliest inhabitants of the Tarim Basin in the Taklamakan Desert were of European and Siberian descent.
The basin, where hundreds of well-preserved mummies have been found since the 1980s, has attracted great attention from scientists worldwide.
Professor Victor Mair of Pennsylvania University claimed in 2006, "From around 1800 B.C. the earliest mummies in the Tarim Basin were exclusively Caucasoid, or Europoid," after he studied DNA samples derived from five bodies unearthed in the basin.
However, Professor Jin Li of Shanghai-based Fudan University, announced in 2007 that the mummies' DNA in the basin's Loulan area, including the 3,800-year-old Loulan Beauty, indicated East Asian, even South Asian origin.
Many archaeologists have accepted that people living in the basin as early as 3,800 years ago, or the Bronze Age, were of European descent, with Asians, mainly from east Asia, only arriving during the Iron Age, Zhou said. "But when the population from Europe and Asia began 'intermarrying' in the area still remains a mystery," she added.
Zhou and her team got DNA samples from the bones and teeth of 20 mummies, around 4,000-year-old. They were all excavated at the Xiaohe cemetery in the basin in 2004 and 2005.
The analyzed DNA profiles included the mitochondrial DNA, which is exclusively passed down through the mother, and the Y chromosome, passed down from father to son.
We found that DNA from five of the seven males derived from their mother, belonged to a lineage that came from Siberia, most likely from south or eastern Siberia, while their Y chromosome indicated European ancestry, Li Chunxiang, another researcher with the team, told Xinhua.
The seven males' Y chromosome had similarities to ancient Europeans who wandered the Eurasian Steppe, stretching roughly 3,000 miles from west to east, mainly in Central Asia.
People of the lineage can be found now in Eastern Europe, Central Asia and Siberia, but rarely in East Asia, Li said.
The mitochondrial DNA of five males and the nine other mummies (four females and five mummies whose gender is unknown) indicated they were related to an ancient lineage that can now be found mostly in modern Siberia, East Asia and Central Asia, Li said.
Their maternal lineage could be traced to Asian populations most likely lived in south Siberia, she said.
Two other females' DNA indicated their maternal ancestors had come from Western Europe.
"Our finding show the European and Siberian tribes began socializing with each other, even intermarrying, almost 4,000 years ago," Zhou said.
But scholars said the Europeans and Siberians might have met and intermarried outside the basin before their immigration into the basin.
"The civilization of the Tarim Basin, according to archaeological findings, arose very late. The 4,000-year-old mummies we found in Xiaohe are believed to be among the earliest inhabitants in the basin. But the Xiaohe people's DNA lineages are over 10,000 years old," Li said.
DNA with both European and Asian markings was also found in south Siberia. People of European origin had spread eastward into that region during the Bronze Age, she said.
The Xiaohe cemetery, 175 km west of the ancient city of Loulan, is located on the ancient Silk Road, once a booming trade route traversing the Asian continent.
The burial ground, with 167 graves, was first explored by Folke Bergman, a Swedish archaeologist in 1934. But it "vanished" until the Xinjiang Archaeological Institute rediscovered it in 2000, Zhou said.
The excavation of the cemetery began in 2002, but only experts with the institute and the Research Center for Chinese Frontier Archaeology of Jilin University were authorized to unearth the lowest layer where the oldest mummies were buried.
"We found 41 graves in this layer, and 37 of them had human remains. The corpses were lying in bottom-up-boat-like coffins. They all had distinctive European appearances and were well-preserved thanks to the dry air and good drainage." She said.
Some mummies unearthed in the Tarim Basin are displayed in a number of museums in Xinjiang, said Idelis Abdurisulu, former director with the Institute of Cultural and Historical Relics and Archaeology of Xinjiang Uygur Autonomous Region.
"The regional museum has six or seven mummies, while others are scattered around Xinjiang in some smaller museums," he said.
In late March, the Bowers Museum in Santa Ana in California began exhibiting two of the Tarim Basin mummies, including Xiaohe Beauty, a 3,800-year-old female, and Qiemo Baby, an infant aged eight to 10 months who died about 2,800 years ago.
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