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 New study: How does Europe become a leading player for software and IT services?
03.04.2017 | Fraunhofer-Institut für System- und Innovationsforschung (ISI)

nachricht Reusable carbon nanotubes could be the water filter of the future, says RIT study
30.03.2017 | Rochester Institute of Technology

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: Can the immune system be boosted against Staphylococcus aureus by delivery of messenger RNA?

Staphylococcus aureus is a feared pathogen (MRSA, multi-resistant S. aureus) due to frequent resistances against many antibiotics, especially in hospital infections. Researchers at the Paul-Ehrlich-Institut have identified immunological processes that prevent a successful immune response directed against the pathogenic agent. The delivery of bacterial proteins with RNA adjuvant or messenger RNA (mRNA) into immune cells allows the re-direction of the immune response towards an active defense against S. aureus. This could be of significant importance for the development of an effective vaccine. PLOS Pathogens has published these research results online on 25 May 2017.

Staphylococcus aureus (S. aureus) is a bacterium that colonizes by far more than half of the skin and the mucosa of adults, usually without causing infections....

Im Focus: A quantum walk of photons

Physicists from the University of Würzburg are capable of generating identical looking single light particles at the push of a button. Two new studies now demonstrate the potential this method holds.

The quantum computer has fuelled the imagination of scientists for decades: It is based on fundamentally different phenomena than a conventional computer....

Im Focus: Turmoil in sluggish electrons’ existence

An international team of physicists has monitored the scattering behaviour of electrons in a non-conducting material in real-time. Their insights could be beneficial for radiotherapy.

We can refer to electrons in non-conducting materials as ‘sluggish’. Typically, they remain fixed in a location, deep inside an atomic composite. It is hence...

Im Focus: Wafer-thin Magnetic Materials Developed for Future Quantum Technologies

Two-dimensional magnetic structures are regarded as a promising material for new types of data storage, since the magnetic properties of individual molecular building blocks can be investigated and modified. For the first time, researchers have now produced a wafer-thin ferrimagnet, in which molecules with different magnetic centers arrange themselves on a gold surface to form a checkerboard pattern. Scientists at the Swiss Nanoscience Institute at the University of Basel and the Paul Scherrer Institute published their findings in the journal Nature Communications.

Ferrimagnets are composed of two centers which are magnetized at different strengths and point in opposing directions. Two-dimensional, quasi-flat ferrimagnets...

Im Focus: World's thinnest hologram paves path to new 3-D world

Nano-hologram paves way for integration of 3-D holography into everyday electronics

An Australian-Chinese research team has created the world's thinnest hologram, paving the way towards the integration of 3D holography into everyday...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Marine Conservation: IASS Contributes to UN Ocean Conference in New York on 5-9 June

24.05.2017 | Event News

AWK Aachen Machine Tool Colloquium 2017: Internet of Production for Agile Enterprises

23.05.2017 | Event News

Dortmund MST Conference presents Individualized Healthcare Solutions with micro and nanotechnology

22.05.2017 | Event News

 
Latest News

How herpesviruses win the footrace against the immune system

26.05.2017 | Life Sciences

Water forms 'spine of hydration' around DNA, group finds

26.05.2017 | Life Sciences

First Juno science results supported by University of Leicester's Jupiter 'forecast'

26.05.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>