Blocking the molecules' function spurs the normally resting cells to begin proliferating strangely - making too much of one kind of cell and not enough of another. Many types of human blood cancers involve a similar disruption in the expression of that same family of molecules.
The blood stem cells' misguided enthusiasm also inhibits their ability to successfully repopulate the immune system of a recipient animal after a bone marrow transplant - a common leukemia treatment.
The discovery is the first to directly link the notorious members of the retinoblastoma family of proteins to the cellular production factories responsible for churning out all the blood and immune cells in the body. "This is an important step in understanding the initiation of human cancer at a cellular level," said Patrick Viatour, PhD, a postdoctoral scholar who performed the research in the laboratory of Julien Sage, PhD.
Sage, assistant professor of pediatrics and of genetics, recently received a SEED grant from the California Institute of Regenerative Medicine to investigate how the retinoblastoma, or Rb, proteins affect human embryonic stem cells. Viatour is the first author of the research, which will be published in the Oct. 9 issue of Cell Stem Cell.
"These studies, and additional experiments from our lab in other tissues and organs, indicate that Rb proteins play a critical role in suppressing tumors originating in adult stem cells populations," said Sage, who is also a member of the Stanford Cancer Center.
The first retinoblastoma protein, pRb, was identified through studies of retinal cancer arising in children in whom the protein is missing or mutated. Since that time, Rb proteins have been shown to be involved in preventing many different types of human cancers. Further study showed that pRb stops a cell from dividing before it has appropriately duplicated and segregated its genetic material - coordinating the complex series of events like a traffic light at a busy intersection.
The protein doesn't work alone, however. Two other family members, p107 and p130, also help carry out the important duties. Their ability to fill in for one another makes it difficult to parse out exactly what the proteins are doing at a molecular level. Unfortunately, laboratory animals missing just one or two family members die soon after birth.
Viatour and Sage devised a way to inhibit, or knock out, the function of all three proteins in adult mice. They genetically engineered animals in which the p107 gene is deleted and the pRb and p130 genes are flanked by pieces of DNA that are recognized and cleaved by a specialized protein called the Cre recombinase. When expressed in blood stem cells, the recombinase snips out the Rb and p130 genes, leaving these stem cells and their progeny - that is, the entire blood system-without any functional Rb family members.
The researchers found that blood, or hematopoetic, stem cells in the mice, which usually hang around quietly waiting to be called into action, began actively proliferating when Rb family members were missing. And while unmodified blood stem cells give rise to two main groups of cells - myeloid and lymphoid - the cells missing the Rb family strongly favored the myeloid lineage.
"The differentiation of these hematopoetic stem cells is clearly defective," said Viatour, who also collaborated with bioinformatician and pediatrician Atul Butte, MD, PhD, and many other Stanford researchers on the work. Butte, an assistant professor of medicine and pediatrics, helped the researchers investigate the gene expression profiles of the blood stem cells. "We found that key myeloid genes were upregulated in the cells, and that lymphoid-associated genes were downregulated," said Viatour. In contrast, the ability of the stem cells to make more of themselves seems unimpaired.
Finally, in an experiment mimicking human bone marrow transplantation, hematopoetic stem cells from the mice missing the Rb family members were no longer able to repopulate the immune systems of animals that had received a lethal dose of radiation.
"It's been known that resting, or quiescent, stem cells are much more likely to be successful candidates for transplantation in both humans and mice than are actively dividing cells," said Viatour. "We now have a good model for understanding why that is."
Viatour and his collaborators plan to continue investigating how the Rb family members affect hematopoetic stem cells. One challenge will be to develop an organ-specific way to knock out Rb family function. They'd also like to find out why differentiated myeloid cells don't also proliferate inappropriately, since they too are missing Rb family members.
Krista Conger | EurekAlert!
Atomic-level motion may drive bacteria's ability to evade immune system defenses
24.04.2017 | Indiana University
Two-dimensional melting of hard spheres experimentally unravelled after 60 years
24.04.2017 | University of Oxford
More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.
Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...
Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.
"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...
The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.
Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...
The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...
Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.
Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...
20.04.2017 | Event News
18.04.2017 | Event News
03.04.2017 | Event News
24.04.2017 | Physics and Astronomy
24.04.2017 | Materials Sciences
24.04.2017 | Life Sciences