Forum für Wissenschaft, Industrie und Wirtschaft

Hauptsponsoren:     3M 
Datenbankrecherche:

 

Researchers discover mutations linked to relapse of childhood leukemia

04.02.2013
Finding emerged from 100 billion RNA nucleotides in 10 children with cancer

After an intensive three-year hunt through the genome, medical researchers have pinpointed mutations that leads to drug resistance and relapse in the most common type of childhood cancer—the first time anyone has linked the disease's reemergence to specific genetic anomalies.

The discovery, co-lead by William L. Carroll, MD, director of NYU Langone Medical Center's Cancer Institute, is reported in a study published online February 3, 2013, in Nature Genetics.

"There has been no progress in curing children who relapse, in spite of giving them very high doses of chemotherapy and bone marrow transplants," said Dr. Carroll.

The discovery suggests how scientists may be able to thwart a dangerous form of acute lymphoblastic leukemia, a rapidly progressing blood-borne cancer that strikes about 6,000 people in the United States every year and accounts for more than one in four pediatric cancers. Eventually, such information could help doctors detect the early emergence of chemotherapy-resistant leukemia cells in patients and switch to a different treatment strategy before the disease can fully reassert itself.

In acute lymphoblastic leukemia, abbreviated ALL, the body's bone marrow produces an abnormally large number of lymphocytes, or white blood cells. Improved treatments have increased the overall cure rate to roughly 80 percent. But Dr. Carroll says the prognosis is especially dire for some 20 percent of patients who relapse.

Medical researchers have suspected that the reemergence of disease could be due to drug resistance, but previous efforts had not uncovered any definitive pathway. For the new study, led by Dr. Carroll and graduate student Julia Meyer, researchers at five U.S. institutions spent three years analyzing multiple bone marrow samples from pediatric ALL patients for more clues to the disease's progression.

With the help of the Children's Oncology Group, a multi-institutional clinical trials consortium supported by the National Cancer Institute, the researchers analyzed the entire transcriptome—or the full sequence of RNA —from 10 children with pediatric B lymphoblastic leukemia, the most common subtype of ALL. RNA is an essential intermediary in the cellular process that uses DNA blueprints to assemble specific proteins, thus a leukemia transcriptome gives researchers a view of all active genes within the cancerous cells.

For each patient, the team pieced together a complete sequence of RNA extracted from the bone marrow at three time points: at diagnosis, during remission, and upon relapse some months or years later. All told, the project required the researchers to sequence, or spell out, 100 billion letters of RNA. By comparing the before and after sequences, the team found that each patient had acquired between one and six mutations that changed the genetic code over the course of the disease. In some cases researchers were able to detect these mutations in a very small subset (0.01 percent) of the tissue samples at diagnosis so that these cells likely expanded because their drug resistant properties provided the leukemia cells with a survival advantage.

In all, the team documented 20 relapse-specific mutations—none of which had previously been implicated in ALL recurrences. Intriguingly, two patients harbored a mutation in the same gene, NT5C2, which encodes a protein that normally regulates some building blocks used to construct DNA but also can degrade an important class of drugs called purine analogues used in ALL therapy.

When the researchers fully sequenced the NT5C2 gene in 61 other cases in which pediatric ALL patients had relapsed, they found five more mutations that altered the gene's coding region. Further experiments suggested that these NT5C2 mutations all increased the protein's enzymatic activity, making the cancer cells more resistant to a chemotherapy treatment designed to force the cells to kill themselves. All seven patients with NT5C2 mutations relapsed within three years of the initial diagnosis—an early, particularly hard-to-treat re-emergence likely mediated by the drug resistance.

Armed with the new knowledge, Dr. Carroll says doctors may be better equipped to identify patients likely to relapse. "We plan to test the feasibility of screening patients during therapy using sophisticated sequencing technology to pick up low-level mutations in NT5C2 and other genes indicating that a mutant clone is growing," he says. His team is researching whether that advance warning could allow doctors to administer separate drugs to beat back the cancer cells, and is also working on a strategy to directly inhibit the mutant enzyme.

The study co-authors include Julia A. Meyer, Jinhua Wang, Laura A. Hogan, Smita Dandekar, Zuojian Tang, Jiri Zavadil, Timothy Cardozo, Elizabeth Raetz, and Debra J. Morrison at NYU Langone Medical Center; Jun J. Yang and William E. Evans at St. Jude Children's Research Hospital; Jay P. Patel and Ross L. Levine at Memorial Sloan-Kettering Cancer Center; Paul Zumbo, Sheng Li, and Christopher E. Mason at Weill Cornell Medical College of Cornell University; and Stephen. P. Hunger at the University of Colorado School of Medicine and Children's Hospital Colorado.

The research was supported by the National Institutes of Health and National Cancer Institute, with additional support from the American Society of Hematology and St. Baldrick's Foundation.

About the NYU Cancer Institute:

The research mission of the NYU Cancer Institute is to discover the origins of cancer and use that knowledge to eradicate the personal and societal burden of cancer in our community and around the world. Fifteen research programs are organized as scientific research programs, focused on the fundamental biology of cancer in general, and as disease-specific research programs centered on individual types of cancer, such as breast or lung cancer. Translational research, a hallmark of the institute, is finding new ways to integrate the extraordinary growth and understanding made in basic research with the ever-growing need for the development of new therapies and approaches in the clinic to a variety of cancers that have remained difficult to treat. To help translate discovery into clinical practice, the NYU Cancer Institute has embarked on five programs that integrate efforts in laboratory investigation and clinical care: cancer targets and novel therapeutics, community and environment, integrative health, molecular oncology/cancer genomics, and immune- and stem-cell-based therapies.

About NYU Langone Medical Center:

NYU Langone Medical Center, a world-class, patient-centered, integrated, academic medical center, is one of the nation's premier centers for excellence in clinical care, biomedical research and medical education. Located in the heart of Manhattan, NYU Langone is composed of four hospitals – Tisch Hospital, its flagship acute care facility; the Hospital for Joint Diseases, one of only five hospitals in the nation dedicated to orthopaedics and rheumatology; Hassenfeld Pediatric Center, a comprehensive pediatric hospital supporting a full array of children's health services; and the Rusk Institute of Rehabilitation Medicine, the world's first university-affiliated facility devoted entirely to rehabilitation medicine– plus NYU School of Medicine, which since 1841 has trained thousands of physicians and scientists who have helped to shape the course of medical history. The medical center's tri-fold mission to serve, teach and discover is achieved 365 days a year through the seamless integration of a culture devoted to excellence in patient care, education and research. For more information, go to www.NYULMC.org.

Christopher Rucas | EurekAlert!
Further information:
http://www.nyumc.org

More articles from Life Sciences:

nachricht Enduring cold temperatures alters fat cell epigenetics
19.04.2018 | University of Tokyo

nachricht Full of hot air and proud of it
18.04.2018 | University of Pittsburgh

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Gammastrahlungsblitze aus Plasmafäden

Neuartige hocheffiziente und brillante Quelle für Gammastrahlung: Anhand von Modellrechnungen haben Physiker des Heidelberger MPI für Kernphysik eine neue Methode für eine effiziente und brillante Gammastrahlungsquelle vorgeschlagen. Ein gigantischer Gammastrahlungsblitz wird hier durch die Wechselwirkung eines dichten ultra-relativistischen Elektronenstrahls mit einem dünnen leitenden Festkörper erzeugt. Die reichliche Produktion energetischer Gammastrahlen beruht auf der Aufspaltung des Elektronenstrahls in einzelne Filamente, während dieser den Festkörper durchquert. Die erreichbare Energie und Intensität der Gammastrahlung eröffnet neue und fundamentale Experimente in der Kernphysik.

Die typische Wellenlänge des Lichtes, die mit einem Objekt des Mikrokosmos wechselwirkt, ist umso kürzer, je kleiner dieses Objekt ist. Für Atome reicht dies...

Im Focus: Gamma-ray flashes from plasma filaments

Novel highly efficient and brilliant gamma-ray source: Based on model calculations, physicists of the Max PIanck Institute for Nuclear Physics in Heidelberg propose a novel method for an efficient high-brilliance gamma-ray source. A giant collimated gamma-ray pulse is generated from the interaction of a dense ultra-relativistic electron beam with a thin solid conductor. Energetic gamma-rays are copiously produced as the electron beam splits into filaments while propagating across the conductor. The resulting gamma-ray energy and flux enable novel experiments in nuclear and fundamental physics.

The typical wavelength of light interacting with an object of the microcosm scales with the size of this object. For atoms, this ranges from visible light to...

Im Focus: Wie schwingt ein Molekül, wenn es berührt wird?

Physiker aus Regensburg, Kanazawa und Kalmar untersuchen Einfluss eines äußeren Kraftfeldes

Physiker der Universität Regensburg (Deutschland), der Kanazawa University (Japan) und der Linnaeus University in Kalmar (Schweden) haben den Einfluss eines...

Im Focus: Basler Forschern gelingt die Züchtung von Knorpel aus Stammzellen

Aus Stammzellen aus dem Knochenmark von Erwachsenen lassen sich stabile Gelenkknorpel herstellen. Diese Zellen können so gesteuert werden, dass sie molekulare Prozesse der embryonalen Entwicklung des Knorpelgewebes durchlaufen, wie Forschende des Departements Biomedizin von Universität und Universitätsspital Basel im Fachmagazin PNAS berichten.

Bestimmte mesenchymale Stamm-/Stromazellen aus dem Knochenmark von Erwachsenen gelten als äusserst viel versprechend für die Regeneration von Skelettgewebe....

Im Focus: Basel researchers succeed in cultivating cartilage from stem cells

Stable joint cartilage can be produced from adult stem cells originating from bone marrow. This is made possible by inducing specific molecular processes occurring during embryonic cartilage formation, as researchers from the University and University Hospital of Basel report in the scientific journal PNAS.

Certain mesenchymal stem/stromal cells from the bone marrow of adults are considered extremely promising for skeletal tissue regeneration. These adult stem...

Alle Focus-News des Innovations-reports >>>

Anzeige

Anzeige

VideoLinks
Industrie & Wirtschaft
Veranstaltungen

124. Internistenkongress in Mannheim: Internisten rücken Altersmedizin in den Fokus

19.04.2018 | Veranstaltungen

DFG unterstützt Kongresse und Tagungen - Juni 2018

17.04.2018 | Veranstaltungen

Stralsunder IT-Sicherheitskonferenz im Mai zum 7. Mal an der Hochschule Stralsund

12.04.2018 | Veranstaltungen

VideoLinks
Wissenschaft & Forschung
Weitere VideoLinks im Überblick >>>
 
Aktuelle Beiträge

124. Internistenkongress in Mannheim: Internisten rücken Altersmedizin in den Fokus

19.04.2018 | Veranstaltungsnachrichten

Aus dem Labor auf die Schiene: Forscher des HI-ERN planen Wasserstoffzüge mit LOHC-Technologie

19.04.2018 | Verkehr Logistik

Neuer Wirkmechanismus von Tumortherapeutikum entdeckt

19.04.2018 | Biowissenschaften Chemie

Weitere B2B-VideoLinks
IHR
JOB & KARRIERE
SERVICE
im innovations-report
in Kooperation mit academics