Over the past two decades, stem cell transplantation has evolved from being an experimental treatment to one that is a viable option for patients with hematologic (blood) malignancies and other life-threatening blood disorders. Researchers and clinicians at the Adult Blood and Marrow Stem Cell Transplantation Program at The Cancer Center at Hackensack University Medical Center are responsible for many of the innovations and techniques used in today’s successful transplants.

Stem cell transplantation researchers in The Cancer Center’s Division of Research recently published results of a study in Blood, the scientific journal of the American Society of Hematology, that may take physicians one step closer to performing customized “designer” stem cell transplants that could lead to better treatment outcomes for patients.

The paper, “Overlap Between in vitro Donor Anti-Host and in vivo Post Transplantation T Cell Response V?2 Utilization: A New Paradigm for Designer Allogeneic Blood and Marrow Transplantation,” was co-authored by Cancer Center researchers Thea Friedman, Ph.D., director of laboratory research; Robert Korngold, Ph.D., chief of the Division of Research; Michele L. Donato, M.D., director of the Blood and Marrow Collection Facility; and Scott D. Rowley, M.D., chief of the Division of Blood and Marrow Stem Cell Transplantation; and researchers from the Kimmel Cancer Center at Thomas Jefferson University in Philadelphia. The paper confirms that a technique - called V?2 (beta) spectratype analysis - can be used to identify mature donor T cells (disease-fighting white blood cells) that can be harmful to the patient.

One of the major risks of an allogeneic transplant (one that uses stem cells removed from a donor) is graft-versus-host disease (GVHD). GVHD is a potentially fatal complication that can occur when mature donor T cells that are transferred along with stem cells from donated blood or bone marrow (the graft) stage an immune response to the “foreign” antigens in the tissues of many organs of the host’s (patient’s) body. These anti-host donor T cells attack the tissues and can cause major organ failure or even death. Past research conducted by Dr. Friedman and Dr. Korngold showed that these GVHD-causing T cells can be removed from the graft to avoid development of disease, and the remaining T cells can mount responses against residual cancer cells like leukemia.

“Following allogeneic blood and marrow transplantation, mature donor T cells can enhance the engraftment process to grow new stem cells, can counteract opportunistic infections, and mount a fight against the cancerous cells but at the risk of developing GVHD,” says Dr. Friedman. “The challenge for researchers is to find a way to enhance the ability of these T cells to destroy residual cancerous cells while avoiding or controlling the T cells’ GVHD response.”

Dr. Friedman continues: “Our V?2 spectratype analysis is a powerful tool for identifying which donor T cell families cause trouble and which are helpful. With this current research, we investigated the potential of using this spectratype approach to compare donor anti-host T cell responses generated in culture with those detected in the patient after transplantation. Our results showed that there was a robust overlap between the in vitro culture responses and those in the patient, indicating that what was seen in vitro was representative of what would happen in the patients.”

The researchers went a step further to evaluate whether the theoretical manipulation of a transplant by removing donor T cells that might launch a GVHD response could prove harmful by also risking the unnecessary loss of beneficial T cells.

“Our results indicated that overall there was a low risk of losing beneficial T cells,” says Dr. Friedman. “This research will enable us to predict before the transplant what kind of a response we would get in a patient after the transplant. Ultimately, our goal is to be able to use this technique to guide us in customizing the transplantation process to obtain better treatment results for patients.”

The research involved 18 patients, ranging in age from 30 to 69 years who were diagnosed with various hematological cancers and serious blood disorders. They were followed by the research team for several years.

This research is funded by grants from the NIH and the Amy Strelzer Manasevit Research Program of the National Marrow Donor Program.

“The studies in stem cell transplantation being conducted at The Cancer Center help to contribute to very favorable outcomes rates for our Adult Blood and Marrow Stem Cell Transplantation Program,” says Andrew L. Pecora, M.D., chairman and executive administrative director.

Each year between 80 and 100 patients undergo allogeneic stem cell transplantation at The Cancer Center at Hackensack University Medical Center. With the addition of autologous stem transplants, the program’s experts perform more than 350 stem cell transplants every year, making it one of the 10 largest in the United States.

The Cancer Center is New Jersey’s largest and the one ranked the best cancer center in the state by New York magazine.

The Cancer Center
http://www.humc.com

Japanese encephalitis (JE), commonly known as brain fever, is one of the prevalent mosquito-borne encephalitis in India and entire South East (SE) Asia. Besides resulting in thousand fatalities each year, JE virus (JEV) infection causes prominent neurological sequelae in approximately one-third of the survivors. Even those patients in the good recovery group commonly encounter psychiatric problems, which include mental retardation, learning disabilities, speech and movement disorders and behavioural abnormalities.

Recent research in National Brain Research Center, Manesar, India by Dr. Anirban Basu and his graduate student, Sulagna Das have shown that JE virus damages the brain in two ways, by not only killing brain cells but by preventing the birth of new cells from neural stem/progenitor cells (NPC) and depleting the NPC pool in the brain. “It’s a double hit to the brain, the JE virus causes brain injury by killing neurons as well as prevents its repair” lead researcher and the senior author of the work Anirban Basu said in a statement.

The children are more vulnerable targets of this virus, which causes massive neuronal loss in the Central Nervous System. “Children are at a dynamic stage of brain development, hence infection at this stage can have devastating effects on mental functions later in life. Our study has tried to explore how JEV infection leads to development of long-term cognitive deficits in the survivors”, says Dr. Anirban Basu who has been working in the neurobiology of JEV infection for the past 4 years. These findings have been published online in a paper in Journal of Neurochemistry for inclusion in a future issue of the journal.

“The breakthrough here is that the JE virus prevents neural stem and progenitor cells in the brain from dividing; it hangs them up,” Basu said. “It’s the first time that a mosquito-borne virus has ever been shown to affect neural stem cells.” The progressive infection in these cells eventually results in decrease in proliferation ability, providing a possible explanation for their diminished pool upon infection,” said Basu. He also went on to state, “The neurological and cognitive deficits in the JE survivors could be related to the drop in NPC cells in the neurogenic region of the brain called the subventricular zone”.

Neural stem/progenitor cells are the saviours of the brain following any insult or infection and via the process of neurogenesis help the recovery process. These cells have the ability to self-renew over lifetime and generate both neurons and glia, which make up the CNS. The initial work with neural stem cells in cell culture dishes interestingly showed that unlike neurons, these stem cells are a resilient population and do not undergo robust cell death upon JEV infection. Instead, the virus lowers the NPC pool by disrupting the growth kinetics and the proliferative ability of these cells. The study was extended in mouse models of JE, where a significant decrease in the actively proliferating NPCs was observed in the subventricular zone or the primary niche of post-natal neurogenesis.

The possible mechanism by which JEV reduces the proliferating NPC pool was also worked out by the scientists utilising the cell cycle studies. Sustained proliferation is a key feature of NPCs, which have to pass through various cell cycle checkpoints and phases of division. Upon JEV infection, these cells halt at the resting phase and fail to proceed to the dividing S-phase. Both cell culture and animal studies indicate that JEV inhibits the DNA synthesis in these cells during progressive infection and induces cycle arrest in them. The researchers went on to show that the virus leads to increased expression of certain checkpoint proteins that block the transition of cells to S-phase, thus preventing the NPCs from multiplying.

Over the years, JE has become a major cause of mortality and morbidity in wide areas of SE Asia. The very high incidence of permanent and disabling neurological sequelae has considerable socioeconomic impact. “Knowing the mechanism, we can start to approach this therapeutically” Basu said. “This indicates that we might eventually treat this form of neurological and psychiatric problems by either ramping up brain repair or protecting the repair mechanism,” Das added.

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Source: Anirban Basu, Ph.D.
Wiley-Blackwell

With today’s hectic lifestyle, where most women are juggling careers, family, relationships, and a host of activities, the idea of possibly facing a serious illness in the future is not something that readily comes to mind — especially when a woman is in the prime of her life. But what most women don’t know, is that the key to treating a number of possibly life-threatening diseases that she, a parent, a sibling or even her children may face in later years, such as osteoporosis, heart disease, stroke, Alzheimer’s and Parkinson’s disease, may be found within her own body — in vital stem cells, which can now be harvested from her own menstrual blood.

Now, thanks to the revolutionary research and technology of C’elle, a service dedicated to providing women with a safe and easy method of collecting and preserving stem cells found in her menstrual fluid each month, even the busiest woman can take control of her future, right in the privacy of her own home. With C’elle’s non-invasive collection process, menstrual cells are processed and cryo-preserved (stored at a very low temperature) for potential cellular therapies that may be used in the future. These self-renewing cells one day may even be used for sports medicine or cosmeceutical treatments, such as anti-aging therapies.

“C’elle enables and empowers a woman to take control of her future health, and possibly of those genetically closest to her, in a fast, painless and stress free way,” said Michelle Kay, Marketing and Sales Manager for C’elle. “We live in exciting times, as science and technology are discovering how extremely valuable menstrual blood stem cells really are, and the enormous treatment potential they represent for future therapies. C’elle’s ongoing research is supporting these promising findings.”

About Cryo-Cell International, Inc. (OTC Bulletin Board: CCEL)

Based in Oldsmar, Florida, with over 150,000 clients worldwide, Cryo-Cell is one of the largest and most established family cord blood banks. ISO 9001:2000 certified and accredited by the AABB, Cryo-Cell operates in a state-of-the-art Good Manufacturing Practice and Good Tissue Practice (cGMP/cGTP)-compliant facility.

Cryo-Cell International, Inc.
http://www.cryo-cell.com

It is “easy” to say Sens. John McCain (R-Ariz.) and Barack Obama (D-Ill.) have different views on “when life begins, use of stem cells and abortion,” but the presidential candidates often are “addressing very different, but related, beginning-of-life issues,” Thomas Marino, a professor of anatomy and cell biology at Temple University’s School of Medicine, writes in a Philadelphia Inquirer opinion piece.

According to Marino, McCain considers these issues from the perspective of the embryo, arguing that it has a right to life, while Obama looks at the issues from the perspective that women have the right to make their own decisions about their reproductive health. The candidates’ decision to talk about “different parts of the story” is “troublesome” in part because “most Americans do not know” about the early stages of human development, Marino writes. According to Marino, many people might not know that only 30% of fertilized eggs result in a birth and that more than half of implanted fertilized embryos “actually complete development while the others normally abort spontaneously.” Many people also do not know the degree to which fertilized embryos develop before a woman knows she is pregnant — including formation of the neural tube and the “first heartbeat,” Marino writes.

“So when the abortion debate occurs, the candidates talk past each other,” Marino writes, adding that the “best approach” would entail the candidates answering two questions — one concerning when a fetus gains protection from society and when “personhood” is established, and the other about who has the right to control a woman’s decision about her reproductive health and if there is a “time when a woman’s reproductive rights can be sacrificed by society for the greater good.” He adds, “Then you might want them to address health care for women, especially those women who cannot afford it. But that is a third issue.” Marino writes that if “we know their thoughts on these issues, we would find out a lot more about the candidates than we know right now” (Marino, Philadelphia Inquirer, 7/17).

Reprinted with kind permission from http://www.nationalpartnership.org. You can view the entire Daily Women’s Health Policy Report, search the archives, or sign up for email delivery here. The Daily Women’s Health Policy Report is a free service of the National Partnership for Women & Families, published by The Advisory Board Company.

© 2008 The Advisory Board Company. All rights reserved.

FDA on Thursday will begin two days of hearings to examine how the agency will regulate human embryonic stem cell therapies, the Wall Street Journal reports. Executives from biotechnology companies, investors, researchers and representatives from patient advocacy groups are expected to attend the hearings, according to FDA officials.

According to the Journal, biotech leaders and investors are seeking more certainty about FDA guidelines for approval of treatments derived from embryonic stem cells and want to ensure that FDA is not averse to approving such treatments for “political reasons.” One company involved in the hearings, Menlo Park, Calif.-based Genron, expects to file an FDA application this summer to begin human testing of a therapy to repair acute spinal injury, the Journal reports. White House spokesperson Tony Fratto said that the Bush administration allows treatments derived from stem cell research and that he is not aware of any objections to the FDA moving forward to approve such treatments despite President Bush’s restrictions on embryonic stem cell research funding (Mundy, Wall Street Journal, 4/10). Federal funding for embryonic stem cell research is allowed only for research using embryonic stem cell lines created on or before Aug. 9, 2001, under a policy announced by Bush on that date. Bush twice has vetoed bills that would have allowed federal funding for research using stem cells derived from human embryos originally created for fertility treatments and willingly donated by patients (Daily Women’s Health Policy Report, 1/29).

Some biotech leaders are concerned that FDA is being pressured into establishing approval guidelines too quickly because there are still concerns regarding ethics, efficacy and safety of the research. There also are concerns that embryonic stem cells could trigger benign tumors. According to Celia Witten, director of FDA’s office of cellular, tissue and gene therapy, one of the agency’s most critical problems will be determining how long such treatments must be tested in animals before entering human trials.

Richard Garr — CEO of Neuralstem, which develops adult stem cell products — said FDA is “nervous” and under “tremendous pressure.” He added that the agency cannot “appear adversarial but they can’t seem to be rolling over for industry either.” Witten said that there is “always an issue” regarding evaluation of safety of “novel technologies” for the agency (Wall Street Journal, 4/10).

Reprinted with kind permission from http://www.nationalpartnership.org. You can view the entire Daily Women’s Health Policy Report, search the archives, or sign up for email delivery here. The Daily Women’s Health Policy Report is a free service of the National Partnership for Women & Families, published by The Advisory Board Company.

© 2007 The Advisory Board Company. All rights reserved.

A few days before the German Federal Parliament reaches a decision on the Stem Cell Act, the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) has reinforced its stance on amending current legislation. “The current qualifying date rule, in particular, strongly impedes German stem cell research,” explained DFG Vice President Professor Jorg Hinrich Hacker, while participating in a live chat session on the DFG website. “The best thing for basic research would be if this qualifying date rule, a deadline which restricts the period in which embryonic stem cell lines are allowed to be imported, were to be abolished altogether, as the DFG recommended in a statement on stem cell research it released 18 months ago,” he emphasised. Hacker recently also became President of the Robert Koch Institute (RKI) in Berlin.

From the point of view of molecular biologists, even moving the deadline would be an improvement compared to the current situation. Hacker also called for an end to the “criminalisation of German researchers.” The current legislation leaves the legal situation of German researchers involved in cooperative projects with stem cell researchers abroad unclear. “This deters young researchers, in particular, from becoming involved in stem cell research.” The DFG is also of the opinion, said Hacker, that stem cell lines should also be used for diagnostic, therapeutic and preventative purposes.

Other topics touched upon during the one-hour live chat session, during which Hacker responded to 27 questions, were the prospects for research on adult stem cells. This, Hacker emphasised, is not viewed by the DFG as standing in contrast to research on embryonic stem cells, but as a logical extension. The recent scientific findings on “induced pluripotent stem cells” were also addressed, a topic which Hacker described as a major breakthrough for molecular biology. He also pointed out, however, that research on human embryonic stem cell lines is indispensable in order to be able to estimate and compare the potential for adult or reprogrammed cells. “Embryonic stem cell lines are more or less the gold standard for studies of this kind.”

Hacker also took a stand on the issue of ovum donation, which is permitted in some countries. This practice is rejected by the DFG and has nothing to do with the production of embryonic stem cell lines. The debate in Germany is essentially about importing cell lines that have been produced abroad and have already been used for research purposes. Culturing new stem cell lines in Germany is already prohibited by the Embryo Protection Law. The DFG has repeatedly spoken out in favour of keeping the Embryo Protection Law in its current form. In answer to another question, Hacker pointed out that any stem cell lines imported from other countries are also subject to strict assessment. They are required to have originated from embryos that were produced for use in reproductive medicine, but for any one of a number of reasons can no longer be used for that purpose. “Here again, no money is allowed to change hands and the couple from whom the cell line originates need to have given their express permission,” Hacker added.

On the question of potential therapeutic uses, another topic addressed during the DFG live chat, Hacker said that “as a general rule of thumb, it takes about ten to fifteen years for a new form of therapy to be developed in biomedicine. If we assume that the first human embryonic stem cell lines were produced ten years ago, then we are now looking at new therapies becoming available in the medium to long term.” He also pointed out, however, that the findings being made in research involving embryonic stem cell lines were also contributing to basic research as well as research aimed at developing new forms of therapy. “Without basic research there is no way we can develop new forms of therapy,” he emphasised.

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Further Information:

Click here to access additional information on stem cell research at the DFG’s website..

A transcript of the DFG live chat with Professor Hacker and DFG statements on stem cell research are available, in German only, at http://www.dfg.de/live.

This release is available in German.

Source: Dr. Eva-Maria Streier
Deutsche Forschungsgemeinschaft

A new study suggests that a genetic fingerprint associated with normal embryonic stem cells may be important for the development and function of cancer stem cells. The research, published by Cell Press in the April 10th issue of Cell Stem Cell, demonstrates that embryonic stem cells and multiple types of human cancer cells share a genetic expression pattern that is repressed in normal differentiated cells, a finding that may have significant clinical implications for cancer therapeutics.

“Self-renewal is a hallmark of stem cells and cancer, but existence of a shared stemness program remains controversial,” explains study co-author, Dr. Howard Y. Chang from Stanford University. Dr. Chang, Dr. Eran Segal from the Weizmann Institute in Israel and their colleagues constructed a gene module map to systematically relate transcriptional programs in embryonic stem cells (ESCs), adult tissue stem cells and human cancers.

The researchers identified two predominant gene modules that distinguish ESCs and adult tissue stem cells. “Importantly, the ESC-like transcriptional program was activated in diverse human epithelial cancers and strongly predicted metastasis and death,” says Dr. Segal. Conversely, the adult tissue stem gene module had an opposite pattern, activated in normal tissues relative to cancer and repressed in various human cancers when compared to normal tissues.

The researchers went on to demonstrate that c-Myc, but not other oncogenes, was sufficient to reactivate the ESC-like program in normal and cancer cells. In primary cells transformed by tumor-inducing genes Ras and I”B”, c-Myc increased the number of tumor-initiating cells that exhibited key properties associated with cancer stem cells and dramatically increased the frequency of tumor formation in mice.”

These findings suggest that activation of an ESC-like transcriptional program in differentiated adult cells may induce pathologic self-renewal characteristics of cancer stem cells. Further, the map of gene modules may prove to be a valuable tool for establishing improved standards for classifying and defining stem cells by using the expression signature modules as “fingerprints” rather than reliance on just a few molecular markers.

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The researchers include David J. Wong, Stanford University, Stanford, CA; Helen Liu, Stanford University, Stanford, CA; Todd W. Ridky, Stanford University, Stanford, CA; David Cassarino, Stanford University, Stanford, CA; Eran Segal, Weizmann Institute, Rehovot, Israel; and Howard Y. Chang, Stanford University, Stanford, CA.

Source: Cathleen Genova
Cell Press

Embryonic stem cell therapies have been proposed for regenerative medicine and tissue replacement after injury or disease. However, the inability of stem cells to efficiently develop into the desired specific cell type - such as muscle, skin, blood vessels, bone or neurons - now limits the potential clinical utility of this therapy.

New research shows that delivering molecules within aggregates of embryonic stem cells via biodegradable microspheres enhances the efficiency and purity of differentiation, which is the process the cells undergo to become more specialized. Details of the microsphere-mediated delivery method, which is funded by the National Science Foundation, were presented at the 235th American Chemical Society national meeting.

“Directing embryonic stem cells to efficiently differentiate into a specific cell type has been challenging to this point,” said Todd McDevitt, an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. “In my lab, we’re trying to better define and then control the environmental cues that regulate the fate and function of the stem cells.”

Because physical interactions between stem cells is critical during normal embryonic development, most laboratory growth methods allow the cells to aggregate in three-dimensional clumps called “embryoid bodies” in order to differentiate. After individual cells aggregate together, hollow internal structures begin to develop and the aggregate becomes larger and more complex over time.

“Many researchers add soluble factors to the culture dish medium to direct differentiation, but this does not accurately mimic the time and location of signaling events present in normal development, and may contribute to heterogeneous differentiation,” said McDevitt. “Our method focuses on incorporating the differentiation factors directly into the cell aggregates in order to have a more controlled mechanism of presentation.”

The research team - which also includes graduate students Richard Carpenedo and Andrés Bratt-Leal and undergraduate students Ross Marklein and Scott Seaman - fabricated biodegradable polymer microspheres that could contain growth factors, proteins or other small molecules.

McDevitt’s team tested the impact of the poly(lactic-co-glycolic acid) (PLGA) microspheres on embryonic stem cell differentiation under different conditions by varying the microsphere-to-cell ratio and speed at which the aggregate cells were mixed with the microspheres. They also included a fluorescent dye in the microspheres so the degree of incorporation of the microspheres within the embryoid bodies could be assessed using fluorescent microscopy and spectroscopy.

The results revealed that the microspheres were incorporated into embryoid bodies under a variety of mixing conditions, but that slower rotary speeds and higher microsphere-to-cell ratios resulted in a greater degree of incorporation.

Next, the researchers compared differentiation of untreated cells, cells mixed with empty microspheres, cells mixed with retinoic acid-loaded microspheres, and cells treated with soluble retinoic acid. Retinoic acid was chosen initially because it is a potent inducer of embryonic stem cell differentiation.

After ten days, approximately 90 percent of the embryoid bodies mixed with retinoic acid-loaded microspheres began to display the hollow structure signifying differentiation, compared to 6 percent of the untreated bodies, 10 percent of the bodies coated with soluble retinoic acid, and 30 percent of the bodies mixed with empty microspheres. In addition, thirty percent of the embryoid bodies mixed with retinoic acid-loaded microspheres were completely hollow in the center, compared to nearly zero percent for the other groups.

“These results suggest that if you can control the signaling by presenting molecules locally on the inside of the embryoid body from biodegradable microspheres, you can effectively change the course and synchrony of differentiation,” said McDevitt.

To examine the cells in more detail, McDevitt teamed with Georgia Tech School of Biology chair John McDonald and research scientist Nathan Bowen to conduct microarray gene expression studies to determine cell phenotype.

The results revealed enhanced expression of fibroblast growth factor 5 (FGF-5) - a marker for primitive ectoderm - in the embryoid bodies mixed with retinoic acid-loaded microspheres compared to the other treatment groups after 10 days. The researchers also confirmed increased or inhibited expression of many additional markers.

“The importance of these findings is that we’ve shown that biomaterial-based approaches to regulate stem cell microenvironments can significantly improve differentiation methods,” said McDevitt. “Our ultimate goal is to improve the efficiency of this differentiation process into specific cell types for cell replacement therapies.”

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Source: Abby Vogel
Georgia Institute of Technology Research News

Leukaemia - cancer of blood or bone marrow - is caused by mutations that allow defective blood cells to accumulate and displace healthy blood. To devise effective therapies it is crucial to know which mutations cause leukaemia and which cell type gives rise to leukaemic cells. Researchers from the European Molecular Biology Laboratory (EMBL) in Italy, the EMBL-European Bioinformatics Institute, UK, and the Universities of Harvard, USA, and Lund, Sweden, have now used genetic engineering to introduce a mutation found in human leukaemia patients into mice. In the current issue of Cancer Cell they report that the mutation causes leukaemia by triggering innate genetic programmes that allow white blood cells to proliferate uncontrollably. The findings have implications for the way leukaemia should be treated.

Blood is generated from a small number of multipotent stem cells that divide, differentiate and give rise to the many different cell types that make up the blood. At the same time they also maintain the pool of stem cells through a process called self-renewal. While differentiating, cells acquire specific properties and functions, but lose the capacity to self-renew in the way stem cells do. Mutations interfering with this process and promoting uncontrolled proliferation of certain blood cells can lead to leukaemia. Researchers of the group of Claus Nerlov at EMBL’s Mouse Biology Unit now prove that a mutation in a protein called C/EBPa causes acute myeloid leukaemia (AML), a type of leukaemia affecting one lineage of white blood cells, in mice.

“10 percent of all patients suffering from AML have this mutation, but we could never be sure if it causes the disease. By precisely reproducing the human mutation in the mouse we now proved a causative relation,” says Peggy Kirstetter, who carried out the research in Nerlov’s lab.

Instead of promoting uncontrolled proliferation of malignant blood stem cells, as often assumed as the cause of leukaemia, the mutation acts on already partially differentiated cells. It reprogrammes these cells to self-renew and to produce countless dysfunctional daughter cells, which displace the healthy blood cells, eventually leading to the inability to transport oxygen around in the body.

“This is the first time that non-stem cell myeloid leukaemia has been generated within a healthy blood system. The findings will have profound implications for our understanding of the development and treatment of leukaemias,” says Nerlov.

Scientists always thought that the mutation was the crucial step leading to leukaemia that should be targeted by drugs. Nerlov and colleagues identified a genetic programme activated in self-renewing leukemic cells, which is shared with similar leukaemias caused by other types of mutations. The findings suggest that the cellular changes that lead to self-renewal are mutation-independent. To develop drugs with a more general efficacy it may therefore be more efficient to target the molecules and pathways shared between different cancer stem cells.

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Source: Anna-Lynn Wegener
European Molecular Biology Laboratory

A unique partnership between industry and academia has led to human clinical trials of a new drug for a rare class of blood diseases called myeloproliferative disorders (MPD), which are all driven by the same genetic mutation and can evolve into leukemia. In just one year, collaborative discoveries by stem cell researchers from the University of California, San Diego, Dana-Farber Cancer Institute, the Mayo Clinic and a San Diego pharmaceutical company, TargeGen, moved from identification of the most promising drug candidate to clinical trials for a new drug to fight this degenerative blood disorder, which affects more than 100,000 Americans.

A study headed by Catriona H.M. Jamieson, M.D. Ph.D., assistant professor of medicine at the University of California, San Diego and Director for Stem Cell Research at Moores UCSD Cancer Center, found an inhibitor that can stop the over-proliferation of blood cells that results in problems with blood clotting, heart attacks and, in some cases, leukemia. Funded in part by a grant from the California Institute for Regenerative Medicine (CIRM), the study will be published in Cancer Cell on April 8, 2008. A parallel study at Harvard Medical School, headed by D. Gary Gilliland, Ph.D., M.D., yielded similar results which will appear in the same issue of Cancer Cell.

“As a clinician, I asked myself who is going to get this disease, and what can we do to stop its progression, instead of waiting until it evolves into a deadly cancer?” said Jamieson. “This project has been so extraordinary, because a small pharmaceutical company took a big chance on a rare disease.”

With major contributions from collaborators Jason Gotlib at Stanford University and Ayalew Tefferi at the Mayo Clinic, the research findings led to development of the inhibitor by TargeGen. That drug is currently being tested in human clinical trials at the UC San Diego School of Medicine, the Mayo Clinic, M.D. Anderson Cancer Center, and the University of Michigan, Stanford and Harvard University Schools of Medicine.

A patient with MPD makes too many blood cells, caused by a mutation expressed in the stem cell, the early stage cell that goes on to differentiate to become either red or white blood cells. In 2007, Jamieson was first author on a paper published in PNAS, outlining the discovery that a mutation in the JAK2 signaling pathway in patients with a type of MPD called polycythemia vera (PV) allows cells to bypass the process which would normally regulate the production of red blood cells. As a result of this defect, the bone marrow produces excessive numbers of red blood cells.

In the current research described in Cancer Cell, the UCSD School of Medicine researchers and collaborators transferred human cord blood stem cells, engineered to contain the mutant JAK2 gene, into mouse models with a suppressed immune system to find whether over-expression of a single gene could drive, or initiate, the disease. These stem cells were introduced directly into the liver, the main site of blood development in the newborn mouse. As a result, the stem cells over-expressing the mutant gene led to overproduction of human red blood cells, and the mice developed a disease that looked like PV.

The researchers corroborated these results by injecting actual stem cells from patients with PV into the same mouse model, achieving similar results. “We found that the JAK2 mutation was necessary and sufficient, by itself, to drive the disease,” Jamieson said.

Theorizing that blocking this mutation would prevent overproduction of red blood cells, TargeGen developed a selective JAK2 inhibitor called TG101348. This therapy was shown in animal studies to halt over-expression of the gene and reverse excessive production of red blood cells. Because TG101348 selectively targets the JAK2 protein that causes the disease, side effects have been minimized.

“Pre-clinical testing at the UCSD and Harvard University Schools of Medicine confirmed the therapeutic potential of TG101348. The compound was rapidly advanced into the current, ongoing human clinical trials being conducted at major research institutions across the country,” said John Hood, Ph.D., Director of Research for TargeGen. “This unique industry-academia collaboration has helped guide a new drug from bench to bedside, from evaluating the compound’s efficacy on cancer stem cells to its evaluation in patients bearing a disease which otherwise has very limited treatment options.”

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Under the auspices of Jamieson, co-first authors Ifat Geron, M.S., and Annelie Abrahamsson, M.S., worked in close collaboration with Kenneth Kaushansky, M.D., chair of the UCSD Department of Medicine; Jason Gotlib, M.D., M.S., at Stanford University School of Medicine; and Ayalew Tefferi, M.D., Department of Medicine at the Mayo Clinic in Minnesota.

Additional contributors to this study include Charlene Barroga, Ph.D. and Edward Kavalerchik, M.D., UCSD Department of Medicine; John Hood, Ph.D., Chi Ching Mak, Glenn Noronha and Richard Soll, Ph.D., TargeGen Inc., San Diego; and Jeffrey Durocher, PH.D., Transgenomic Inc., Gaithersberg, MD. The study was funded in part by the California Institute for Regenerative Medicine and the Mizrahi Family Foundation, the National Institutes of Health (K23HL04409) and an unrestricted gift from TargeGen Inc.

Source: Debra Kain
University of California - San Diego