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Scientists identify key gene that protects against leukemia
April 09, 2009Researchers have identified a gene that controls the rapid production and differentiation of the stem cells that produce all blood cell types-a discovery that could eventually open the door to more streamlined treatments for leukemia and other blood cancers, in which blood cells proliferate out of control.
Additionally, in investigating the mechanisms of this gene, the scientists uncovered evidence that could lead to a protocol for bone marrow transplants that could boost the chance of a cure in some patients.
The research, led by Emmanuelle Passegué, PhD, of the University of California, San Francisco, demonstrates that the JunB gene is at the center of a complex network of molecular and environmental signals that regulate the proliferation and differentiation of hematopoietic stem cells, the multipotent, self-renewing cells that give rise to all blood cell types.
In the study published April 7, 2009, in the journal Cancer Cell, Passegué's team studied the behavior of JunB-deficient HSCs in both the culture dish and when transplanted into mice.In every case in which engraftment of the HSCs occurred in the mice, the scientists noted a progressive expansion of the myeloidlineage, which constitutes a type of mature white blood cell that fights infection. This expansion led by 6 to 12 months post-transplantation to the development of a myeloproliferative disease, which can evolve to leukemia. The finding indicated that the proliferating JunB-deficient HSCs causes leukemia.
Like traffic lights, which limit speed, direct the flow of vehicles and prevent accidents, JunB curtails both the rate at which HSCs are proliferating and the rate of differentiation toward the myeloid lineage that ultimately results in leukemia. The striking analogy inspired the image for the cover of Cancer Cell's April 7 issue.
Without JunB, HSCs lose their ability to respond to signals from the protein receptors Notch and TGF-beta, which reside on the cells' surface and play critical roles in determining cell fate.
"By uncovering this mechanism, we might one day be able to determine the difference between normal HSCs and leukemic stem cells in gene regulatory networks. This could allow us to develop more targeted therapies. These kinds of therapeutic applications are still down the road, but they can happen very quickly in the blood/leukemia field," says Passegué.
Passegué's study represents a turnabout from other research, which has demonstrated that mutated HSC that cause leukemia burn out at a faster rate than normal HSCs. In contrast, this study shows that JunB does not effect the cells' potential for unlimited self-renewal.
The researchers demonstrated this by treating both JunB-deficient mice and control mice with the powerful chemotherapy drug 5-FU, which was given to deplete regenerating HSCs. As expected, JunB-deficient mice consistently displayed higher levels of myeloid lineage than the control group, indicating constant regeneration of a myeloproliferative disease from JunB-deficient HSCs that persisted after treatment. When researchers compared survival rates of the animals during several cycles of treatment, they found little difference between the two groups, indicating that JunB-deficient HSCsdo not exhaust faster than the control HSCs.
In tracking the differences between the JunB-deficient mice and the control group, it became apparent to the researchers that purity of HSCs was a key factor in determining the success of engraftment. Initially, the scientists were struck by the disparity in engraftment between the JunB-deficient HSCs and the control HSCs. But with the use of SLAM cells, a highly purified HSC population, they found that the two groups displayed in fact identical engraftment.
This finding may have important ramifications for patients undergoing bone marrow transplants, for leukemia, lymphoma, multiple myeloma and certain cancers.
"Currently, patients undergoing bone marrow transplants may not be getting enough of the quiescent transplanted HSCs that are optimal for successful engraftment," says Passegué. Using a highly purified HSC population could be more beneficial."
Senior author Passegué and first author Marianne Santaguida, PhD, are from the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF. Co-authors from the same center are Koen Schepers, PhD, and Bryan King.
Other co-authors are Benjamin Braun, MD, PhD, and Amit Sabnis, MD, of the UCSF Department of Pediatrics; E. Camilla Forsberg, PhD, of the Institute for Biology of Stem Cells at University of California, Santa Cruz, and Joanne Attema, PhD, of the Institute for Experimental Medical Science at Lund University, Sweden.
Research was funded by grants from the Concern Foundation, UCSF Research Evaluation and Allocation Committee and the NIH.
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. For further information, visit http://www.ucsf.edu.
For more information about the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF, see http://irm.ucsf.edu/.
The University of California, San Francisco
In the study published April 7, 2009, in the journal Cancer Cell, Passegué's team studied the behavior of JunB-deficient HSCs in both the culture dish and when transplanted into mice.In every case in which engraftment of the HSCs occurred in the mice, the scientists noted a progressive expansion of the myeloidlineage, which constitutes a type of mature white blood cell that fights infection. This expansion led by 6 to 12 months post-transplantation to the development of a myeloproliferative disease, which can evolve to leukemia. The finding indicated that the proliferating JunB-deficient HSCs causes leukemia.
Like traffic lights, which limit speed, direct the flow of vehicles and prevent accidents, JunB curtails both the rate at which HSCs are proliferating and the rate of differentiation toward the myeloid lineage that ultimately results in leukemia. The striking analogy inspired the image for the cover of Cancer Cell's April 7 issue.
Without JunB, HSCs lose their ability to respond to signals from the protein receptors Notch and TGF-beta, which reside on the cells' surface and play critical roles in determining cell fate.
"By uncovering this mechanism, we might one day be able to determine the difference between normal HSCs and leukemic stem cells in gene regulatory networks. This could allow us to develop more targeted therapies. These kinds of therapeutic applications are still down the road, but they can happen very quickly in the blood/leukemia field," says Passegué.
Passegué's study represents a turnabout from other research, which has demonstrated that mutated HSC that cause leukemia burn out at a faster rate than normal HSCs. In contrast, this study shows that JunB does not effect the cells' potential for unlimited self-renewal.
The researchers demonstrated this by treating both JunB-deficient mice and control mice with the powerful chemotherapy drug 5-FU, which was given to deplete regenerating HSCs. As expected, JunB-deficient mice consistently displayed higher levels of myeloid lineage than the control group, indicating constant regeneration of a myeloproliferative disease from JunB-deficient HSCs that persisted after treatment. When researchers compared survival rates of the animals during several cycles of treatment, they found little difference between the two groups, indicating that JunB-deficient HSCsdo not exhaust faster than the control HSCs.
In tracking the differences between the JunB-deficient mice and the control group, it became apparent to the researchers that purity of HSCs was a key factor in determining the success of engraftment. Initially, the scientists were struck by the disparity in engraftment between the JunB-deficient HSCs and the control HSCs. But with the use of SLAM cells, a highly purified HSC population, they found that the two groups displayed in fact identical engraftment.
This finding may have important ramifications for patients undergoing bone marrow transplants, for leukemia, lymphoma, multiple myeloma and certain cancers.
"Currently, patients undergoing bone marrow transplants may not be getting enough of the quiescent transplanted HSCs that are optimal for successful engraftment," says Passegué. Using a highly purified HSC population could be more beneficial."
Senior author Passegué and first author Marianne Santaguida, PhD, are from the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF. Co-authors from the same center are Koen Schepers, PhD, and Bryan King.
Other co-authors are Benjamin Braun, MD, PhD, and Amit Sabnis, MD, of the UCSF Department of Pediatrics; E. Camilla Forsberg, PhD, of the Institute for Biology of Stem Cells at University of California, Santa Cruz, and Joanne Attema, PhD, of the Institute for Experimental Medical Science at Lund University, Sweden.
Research was funded by grants from the Concern Foundation, UCSF Research Evaluation and Allocation Committee and the NIH.
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. For further information, visit http://www.ucsf.edu.
For more information about the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF, see http://irm.ucsf.edu/.
The University of California, San Francisco
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UAB Researchers Discover Antibody Receptor Identity, Propose Renaming Immune-System Gene
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U of M researchers find 2 units of umbilical cord blood reduce risk of leukemia recurrence
A new study from the Masonic Cancer Center, University of Minnesota shows that patients who have acute leukemia and are transplanted with two units of umbilical cord blood (UCB) have significantly reduced risk of the disease returning.
Aileron collaborates study in Nature: Stapled peptides inhibit Notch1 transcription factor
This research validates the potential for Stapled Peptides to modulate key intracellular biological targets, such as transcription factors, that have not been addressable with current small molecule or biologic drug modalities.
Researchers 'notch' a victory toward new kind of cancer drug
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FDA approved leukemia drugs shows promise in ovarian cancer cells
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First use of antibody and stem cell transplantation to successfully treat advanced leukemia
For the first time, researchers at Fred Hutchinson Cancer Research Center have reported the use of a radiolabeled antibody to deliver targeted doses of radiation, followed by a stem cell transplant, to successfully treat a group of leukemia and pre-leukemia patients for whom there previously had been no other curative treatment options.
American Dietetic Association Releases Updated Position Paper Promoting and Supporting Breastfeeding
The American Dietetic Association has released an updated position paper on breastfeeding that details health benefits for both infants and mothers and encourages promotion of breastfeeding whenever possible.
Drug shows promise in treating dangerous complication of erectile disorder
Thousands of men are afflicted with an embarrassing and painful condition that triggers spontaneous, long-lasting erections. There are limited treatment options, but a solution could be on the way thanks to new research at The University of Texas Health Science Center at Houston.
Brain tumors in childhood leave a lasting mark on cognition, life status
Brain tumors in childhood cast a long shadow on survivors. The first study of the lasting impact of these tumors -- the most common solid malignancies in childhood -- shows that survivors have ongoing cognitive problems.
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