Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Blood stem cell, leukemia link illuminated in UCSF-led study

17.08.2010
A UCSF-led team has discovered at least one key reason why blood stem cells are susceptible to developing the genetic mutations that can lead to adult leukemia. Their finding also may explain, they say, why some other age-related hematological disorders develop.

The study, reported in “Cell Stem Cell” (Aug. 6, 2010) and reviewed in Cell Stem Cell and Cell, opens a new frontier for studying the molecular underpinnings of adult leukemia.

The discovery also suggests a possible therapeutic strategy, the scientists say, for reducing the risk of leukemia that results from chemotherapy used to treat solid tumors.

Finally, it may explain why other types of adult stem cells are susceptible to accumulating potentially lethal mutations.

Blood stem cells, located in the bone marrow, give rise to all blood cells of the body, such as red blood cells, white blood cells, and platelets. During fetal development, the stem cells specialize, or differentiate, into these various cell types. During life, they incessantly repeat the process, replacing old or depleted blood cells. The population also continuously self-renews.

Like most other adult stem cells, blood stem cells maintain a resting, or “quiescent,” state when they are not differentiating or self-renewing. They do so to minimize stress caused by cellular respiration and errors in DNA replication, which can lead to DNA damage.

In the current study, conducted in the culture dish and mice, the team set out to determine if blood stem cells in the quiescent state were at greater risk for incurring genetic mutations in the process of repairing damaged DNA than were proliferating cells. Scientists have known that defects in DNA repair processes are associated with cancers, though they have known little about the mechanisms.

The team determined that both quiescent and proliferating blood stem cells have protective mechanisms ensuring their survival in response to exposure to ionizing irradiation, as occurs from such sources as the sun and X-rays.

However, they discovered that quiescent and proliferating blood stem cells initiate different types of DNA repair mechanisms once the cells have survived. Proliferating blood stem cells undergo DNA repair using a high-fidelity process known as homologous recombination, which has a minimal risk of acquiring mutations, as documented in the study.

Quiescent cells, on the other hand, use a mechanism known as nonhomologous end joining-mediated DNA repair, which often leads to misrepair of double strand breaks in the DNA. Such error prone repair can result in chromosomal deletions, insertions or translocations and subsequent genomic instability that can contribute to hematopoetic abnormalities. This, too, was documented in the study. The quiescent cells are limited to using the error prone NHEJ mechanism because of the constraint imposed by their cell cycle on the molecular composition of their DNA repair machinery.

“Our results demonstrate that quiescence is a double-edged sword, protecting hematopoetic stem cells from cellular stress but rendering them intrinsically vulnerable to mutagenesis following DNA damage,” says senior author Emmanuelle Passegué, PhD, associate professor of medicine (division of hematology/oncology) and a member of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF.

The finding, the result of “heroic” research begun four years ago by Mary Mohrin, a graduate student in the Passegué lab, upturns current dogma, says Passegué. “The thinking has been that blood stem cells must proliferate to acquire the mutations that drive tumor development. This work says, ‘not so.’”

While the repair mechanism used by the quiescent cells is defective, it is not detrimental for the body in evolutionary terms, says Passegué. “The blood stem cell system is designed to support the body through its sexually reproductive years, so the genome can be passed along. The ability of quiescent blood stem cells to quickly undergo DNA repair supports this goal, and the risk of acquiring enough mutations in these years to cause genomic instability is minimal.”

The problem occurs with age, she notes, as the cells have spent a lifetime responding to naturally occurring insults and the effects of X-rays, medications and chemotherapies.

On the positive side, she says, the finding suggests a strategy for reducing the risk of leukemia resulting from chemotherapy used to treat solid tumors. “Existing drugs, such as G-CSF and prostaglandins, could be used to induce hematopoetic stem cells to proliferate prior to the use of therapy with DNA damaging agents,” she says. “This could enhance DNA repair fidelity and reduce the risk of leukemia development.” She is discussing this possible tactic with UCSF clinical researchers.

On a lighter note, she reflects, “our discovery may be good PR for blood donations.” While acknowledging her rationale is a bit speculative, she says, “Bleeding is a good way to keep the blood stem cell pool in an active, or proliferative, state.”

Other UCSF co-authors were Matthew R. Warr and Keegan Barry-Holson, of the Passegué lab. Co-authors from other institutions were Emer Bourke and Ciaran G. Morrison, of the National University of Ireland, Galway, David Alexander, of the University of California, Santa Cruz, and Michelle M. Le Beau, of the University of Chicago.

Lead author Mohrin is funded by a pre-doctoral training grant from the California Institute for Regenerative Medicine. Other funding for the study included a CIRM New Investigator Award and Rita Allen Scholar Award to Passegué, a U.S. Public Health Service grant to Le Beau, and a Science Foundation Ireland award to Morrison.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.

Related links:

Cell Stem Cell paper (Aug. 6, 2010 print edition)
http://www.cell.com/cell-stem-cell/fulltext/S1934-5909%2810%2900329-2
Cell Stem Cell review (Aug. 6, 2010 print edition)
http://www.cell.com/cell-stem-cell/fulltext/S1934-5909%2810%2900340-1
Cell review (Aug. 6, 2010 print edition)
http://www.cell.com/fulltext/S0092-8674%2810%2900834-2
UCSF news release on Passegué lab Cancer Cell paper, 2009
http://news.ucsf.edu/releases/scientists-identify-key-gene-that-protects-against-leukemia
Passegué Cancer Cell paper 2009
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WWK-4W0YDHT-F&_user=4430&_coverDate=04%2F07%2F2009&_rdoc=1&_fmt=high&_orig=search&_sort=d&_docanchor=&view=c&

_acct=C000059594&_version=1&_urlVersion=0&_userid=4430&md5=605488ff1f5da5a3fb0ad5a791a38359

Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research
http://stemcell.ucsf.edu/

Jennifer O'Brien | EurekAlert!
Further information:
http://www.ucsf.edu

More articles from Studies and Analyses:

nachricht Multi-year study finds 'hotspots' of ammonia over world's major agricultural areas
17.03.2017 | University of Maryland

nachricht Diabetes Drug May Improve Bone Fat-induced Defects of Fracture Healing
17.03.2017 | Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke

All articles from Studies and Analyses >>>

The most recent press releases about innovation >>>

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

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

Im Focus: Researchers Imitate Molecular Crowding in Cells

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

Pulverizing electronic waste is green, clean -- and cold

22.03.2017 | Materials Sciences

Astronomers hazard a ride in a 'drifting carousel' to understand pulsating stars

22.03.2017 | Physics and Astronomy

New gel-like coating beefs up the performance of lithium-sulfur batteries

22.03.2017 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>