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 Cells cling and spiral 'like vines' in first 3-D tissue scaffold for plants
27.08.2015 | University of Cambridge

nachricht Cellular contamination pathway for plutonium, other heavy elements, identified
27.08.2015 | DOE/Lawrence Berkeley National Laboratory

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Optische Schalter - Lernen mit Licht

Einem deutsch-französischen Team ist es gelungen, einen lichtempfindlichen Schalter für Nervenzellen zu entwickeln. Dies ermöglicht neue Einblicke in die Funktionsweise von Gedächtnis und Lernen, aber auch in die Entstehung von Krankheiten.

Lernen ist nur möglich, weil die Verknüpfungen zwischen den Nervenzellen im Gehirn fortwährend umgebaut werden: Je häufiger bestimmte Reizübertragungswege...

Im Focus: What would a tsunami in the Mediterranean look like?

A team of European researchers have developed a model to simulate the impact of tsunamis generated by earthquakes and applied it to the Eastern Mediterranean. The results show how tsunami waves could hit and inundate coastal areas in southern Italy and Greece. The study is published today (27 August) in Ocean Science, an open access journal of the European Geosciences Union (EGU).

Though not as frequent as in the Pacific and Indian oceans, tsunamis also occur in the Mediterranean, mainly due to earthquakes generated when the African...

Im Focus: Membranprotein in Bern erstmals entschlüsselt

Dreidimensionale (3D) Atommodelle von Proteinen sind wichtig, um deren Funktion zu verstehen. Dies ermöglicht unter anderem die Entwicklung neuer Therapieansätze für Krankheiten. Berner Strukturbiologen ist es nun gelungen, die Struktur eines wichtigen Membranproteins zu entschlüsseln – dies gelingt relativ selten und ist eine Premiere in Bern.

Membranproteine befinden sich in den Wänden der Zellen, den Zellmembranen, und nehmen im menschlichen Körper lebenswichtige Funktionen wahr. Zu ihnen gehören...

Im Focus: Quantenbeugung an einem Hauch von Nichts

Die Quantenphysik besagt, dass sich auch massive Objekte wie Wellen verhalten und scheinbar an vielen Orten zugleich sein können. Dieses Phänomen kann nachgewiesen werden, indem man diese Materiewellen an einem Gitter beugt. Eine europäische Kollaboration hat nun erstmals die Delokalisation von massiven Molekülen an einem Gitter nachgewiesen, das nur noch eine einzige Atomlage dick ist. Dieses Experiment lotete die technischen Grenzen der Materiewellentechnologie aus und knüpft dabei an ein Gedankenexperiment von Bohr und Einstein an. Die Ergebnisse werden aktuell im Journal "Nature Nanotechnology" veröffentlicht.

Die quantenmechanische Wellennatur der Materie ist die Grundlage für viele moderne Technologien, wie z. B. die höchstauflösende Elektronenmikroskopie, die...

Im Focus: Auf Zeitreise in die Vergangenheit von Randmeeren: IOW-Expedition erkundet kanadische Küstengewässer

Wie und warum haben sich küstennahe Gewässer im Lauf der letzten Jahrzehnte und Jahrhunderte verändert? Wie kann man unterscheiden, welche Prozesse natürlicher Weise dazu beigetragen haben und welche durch den Einfluss des Menschen angestoßen wurden? Lässt sich die Ostsee als intensiv erforschtes Modell mit anderen Randmeeren vergleichen? Diese Fragen stehen im Mittelpunkt der Expedition der MARIA S. MERIAN, die am 25. August 2015 im kanadischen Halifax startet und das Forschungsschiff unter Federführung des Leibniz-Instituts für Ostseeforschung Warnemünde (IOW) in den Sankt-Lorenz-Strom und den Sankt-Lorenz-Golf und anschließend entlang der Küste von Labrador bis in die Hudson-Straße führt.

Mit an Bord sind insgesamt 25 WissenschaftlerInnen, darunter 15 vom IOW und 10 weitere
kanadische und U.S.-amerikanische Forschungspartner. Koordiniert wird...

Alle Focus-News des Innovations-reports >>>

Anzeige

Anzeige

IHR
JOB & KARRIERE
SERVICE
im innovations-report
in Kooperation mit academics
Veranstaltungen

Konzepte gegen Fachkräftemangel: Demografiekonferenz in Halle

27.08.2015 | Veranstaltungen

Neue Lösungen für Passivierung und Wafering: Fraunhofer CSP auf der EU PVSEC

27.08.2015 | Veranstaltungen

Tagung des CHF-KL: Industrie 4.0 und Digitalisierung - Herausforderungen für das Personalmanagement

27.08.2015 | Veranstaltungen

 
B2B-VideoLinks
Weitere VideoLinks >>>
Aktuelle Beiträge

Tiefer Blick in die Mechanismen von Halos

27.08.2015 | Physik Astronomie

Forschungsteam der Universität Hamburg beobachtet Auferstehung eines kosmischen (Radio-)Phönix

27.08.2015 | Physik Astronomie

Erfolgreiche Bor-Dotierung von Graphen-Nanoband

27.08.2015 | Physik Astronomie