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UCLA Researchers Unlock Protein Key to Harnessing Regenerative
Power of Blood Stem Cells to Fight Cancer
Posted Date: 11/24/2014 9:30 AM Faculty: John P. Chute, M.D.
STORY HIGHLIGHTS
UCLA scientists have discovered a protein which is integral to the regulation of human blood stem cell regeneration Study revealed that stem cells which lack the protein have markedly increased ability to replicate in the natural environment and following transplantation.
Discovery provides new understanding of human stem cell self-renewal and paves the way for targeted therapies against cancer and other diseases. In a study led by UCLA Jonsson Comprehensive Cancer Center member Dr. John Chute, scientists have for the first time identified a unique protein that plays a key role in regulating blood stem cell replication in humans.
This discovery lays the groundwork for a better understanding of how this protein controls blood stem cell growth and regeneration, and could lead to the development of more effective therapies for a wide range of blood diseases and cancers.
The study was published online November 21, 2014 ahead of print in the Journal of Clinical Investigation.
Hematopoietic stem cells (HSCs) are the blood-forming cells that have the remarkable capacity to both self-renew and give rise to all of the differentiated cells (fully developed cells) of the blood system. HSC transplantation provides curative therapy for thousands of patients annually. However, little is known about the process through which transplanted HSCs replicate following their arrival in human bone marrow.
In this study, the authors showed that a cell surface protein called protein tyrosine phosphatase-sigma (PTP-sigma) regulates the critical process called engraftment, meaning how HSCs start to grow and make health blood cells after transplantation.
Mamle Quarmyne, a graduate student the lab of Dr. Chute and first author of the study, demonstrated that PTP-sigma is produced (expressed) on a high percentage of mouse and human HSCs. She showed further that genetic deletion of PTP-sigma in mice markedly increased the ability of HSCs to engraft in transplanted mice.
In a complementary study, she demonstrated that selection of human blood HSCs which did not express PTP-sigma led to a 15-fold increase in HSC engraftment in transplanted immune-deficient mice. Taken together, these studies showed that PTP-sigma suppresses normal HSC engraftment capacity and targeted blockade of PTP-sigma can substantially improve mouse and human HSC engraftment after transplantation.
Chute and colleagues showed further that PTP-sigma regulates HSC function by suppressing a protein, RAC1, which is known to promote HSC engraftment after transplantation.
"These findings have tremendous therapeutic potential since we have identified a new receptor on HSCs, PTP-sigma, which can be specifically targeted as a means to potently increase the engraftment of transplanted HSCs in patients," said Chute, senior author of the study and UCLA Professor of Hematology/Oncology and Radiation Oncology. "This approach can also potentially accelerate hematologic recovery in cancer patients receiving chemotherapy and/or radiation, which also suppress the blood and immune systems."
Chute's team is now working with fellow UCLA researchers to test small molecules for their ability to specifically inhibit PTP-sigma on blood stem cells. If these studies are successful, they aim to translate these findings into clinical trials in the near future.
This research was supported by funding from the National Institute of Allergy and Infectious Diseases and National Heart, Lung, and Blood Institute.
About UCLA's Jonsson Comprehensive Cancer Center
UCLA's Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation's largest comprehensive cancer centers, the Jonsson center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2014, the Jonsson Cancer Center was named among the top 10 cancer centers nationwide by U.S. News & World Report, a ranking it has held for 14 years.
For more information on the Jonsson Cancer Center, visit our website at http://www.cancer.ucla.edu
Power of Blood Stem Cells to Fight Cancer
Posted Date: 11/24/2014 9:30 AM Faculty: John P. Chute, M.D.
STORY HIGHLIGHTS
UCLA scientists have discovered a protein which is integral to the regulation of human blood stem cell regeneration Study revealed that stem cells which lack the protein have markedly increased ability to replicate in the natural environment and following transplantation.
Discovery provides new understanding of human stem cell self-renewal and paves the way for targeted therapies against cancer and other diseases. In a study led by UCLA Jonsson Comprehensive Cancer Center member Dr. John Chute, scientists have for the first time identified a unique protein that plays a key role in regulating blood stem cell replication in humans.
This discovery lays the groundwork for a better understanding of how this protein controls blood stem cell growth and regeneration, and could lead to the development of more effective therapies for a wide range of blood diseases and cancers.
The study was published online November 21, 2014 ahead of print in the Journal of Clinical Investigation.
Hematopoietic stem cells (HSCs) are the blood-forming cells that have the remarkable capacity to both self-renew and give rise to all of the differentiated cells (fully developed cells) of the blood system. HSC transplantation provides curative therapy for thousands of patients annually. However, little is known about the process through which transplanted HSCs replicate following their arrival in human bone marrow.
In this study, the authors showed that a cell surface protein called protein tyrosine phosphatase-sigma (PTP-sigma) regulates the critical process called engraftment, meaning how HSCs start to grow and make health blood cells after transplantation.
Mamle Quarmyne, a graduate student the lab of Dr. Chute and first author of the study, demonstrated that PTP-sigma is produced (expressed) on a high percentage of mouse and human HSCs. She showed further that genetic deletion of PTP-sigma in mice markedly increased the ability of HSCs to engraft in transplanted mice.
In a complementary study, she demonstrated that selection of human blood HSCs which did not express PTP-sigma led to a 15-fold increase in HSC engraftment in transplanted immune-deficient mice. Taken together, these studies showed that PTP-sigma suppresses normal HSC engraftment capacity and targeted blockade of PTP-sigma can substantially improve mouse and human HSC engraftment after transplantation.
Chute and colleagues showed further that PTP-sigma regulates HSC function by suppressing a protein, RAC1, which is known to promote HSC engraftment after transplantation.
"These findings have tremendous therapeutic potential since we have identified a new receptor on HSCs, PTP-sigma, which can be specifically targeted as a means to potently increase the engraftment of transplanted HSCs in patients," said Chute, senior author of the study and UCLA Professor of Hematology/Oncology and Radiation Oncology. "This approach can also potentially accelerate hematologic recovery in cancer patients receiving chemotherapy and/or radiation, which also suppress the blood and immune systems."
Chute's team is now working with fellow UCLA researchers to test small molecules for their ability to specifically inhibit PTP-sigma on blood stem cells. If these studies are successful, they aim to translate these findings into clinical trials in the near future.
This research was supported by funding from the National Institute of Allergy and Infectious Diseases and National Heart, Lung, and Blood Institute.
About UCLA's Jonsson Comprehensive Cancer Center
UCLA's Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation's largest comprehensive cancer centers, the Jonsson center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2014, the Jonsson Cancer Center was named among the top 10 cancer centers nationwide by U.S. News & World Report, a ranking it has held for 14 years.
For more information on the Jonsson Cancer Center, visit our website at http://www.cancer.ucla.edu