 |
|
Leukemic cells find safe haven in bone marrow
March 23, 2007St. Jude study shows mesenchymal cells in bone marrow supply leukemic cells with the amino acid asparagine, restoring this critical nutrient when it is depleted by the cancer drug asparaginase
The cancer drug asparaginase fails to help cure some children with acute lymphoblastic leukemia (ALL) because molecules released by certain cells in the bone marrow counteract the effect of that drug, according to investigators at St. Jude Children's Research Hospital.
The researchers showed that mesenchymal cells in the bone marrow create a protective niche for leukemic cells by releasing large amounts of asparagine, an amino acid that nearby leukemic cells must have to survive but do not make efficiently. This extra supply of asparagine helps leukemic cells survive treatment with asparaginase, a drug that normally would deplete their supply of this vital nutrient, the researchers reported. Mesenchymal cells give rise to a variety of different tissues, such as osteoblasts (bone-building cells) and chondrocytes (cartilage-building cells), and form the nurturing environment where normal blood cells and leukemic cells grow.
"Leukemic cells that resist asparaginase and survive in this protective niche of the bone marrow might be the reason that leukemia recurs in some children who have been treated with this drug," said Dario Campana, M.D., Ph.D., a member of the St. Jude Oncology and Pathology departments.
Campana is senior author of the report that appears in the online pre-publication issue of "The Journal of Clinical Investigation."
"Our findings indicate that the level of activity of the "ASNS" gene in the mesenchymal cells is key to protecting leukemic cells in the bone marrow from asparaginase," Campana said. "This insight will help researchers find ways to disrupt this safe haven for leukemic cells that need asparagine," added James R. Downing, M.D., St. Jude scientific director and chair of the Pathology department. Downing is a co-author of "The Journal of Clinical Investigation" paper. The "ASNS" gene controls production of the enzyme asparagine synthetase (ASNS), which leukemic cells use to make asparagine.
The study's findings also suggest that drugs now being developed to block ASNS should be tested to see if they also prevent mesenchymal cells from making this amino acid. In addition, the ability of mesenchymal cells to make asparagine might be decreased by cancer drugs that are already known to disrupt the activity of those cells.
"Because asparaginase is so widely used to treat ALL, this new insight into how mesenchymal cells protect leukemic cells is very important," said Ching-Hon Pui, M.D., chair of the Oncology department and American Cancer Society Professor at St. Jude. "The more we learn about the molecular interactions between these cells, the more likely we'll be able to enhance the anti-leukemic action of asparaginase and perhaps other anti-leukemic drugs as well," said Pui, a co-author of the paper. "That would reduce the recurrence rate of ALL and continue our successful efforts to increase the survival rate of ALL."
Previous research at St. Jude and elsewhere had shown that direct contact with bone marrow mesenchymal cells is essential for the long-term survival and multiplication of leukemic lymphoblasts. In the current study, the team found that the gene for ASNS was more than 20 times active in producing this enzyme in mesenchymal cells than in ALL cells.
Experiments performed by co-authors Shotaro Iwamoto, M.D., and Keichiro Mihara, postdoctoral fellows in Campana's laboratory, demonstrated that ALL cells from different patients became much more resistant to asparaginase when cultured on top of a layer of mesenchymal cells. In order to determine whether it was the high levels of asparagine released by mesenchymal cells that protected ALL cells from asparaginase, the St. Jude team repeated the experiment, but blocked the ability of mesenchymal cells to make the ASNS enzyme and produce asparagine. In this case, the protective effect of mesenchymal cells was eliminated. Conversely, when the researchers caused the ASNS gene to work overtime making asparagine, the ability of the mesenchymal cells layer to protect the ALL cells was significantly enhanced. The team also showed that the more actively "ASNS" genes produced ASNS in mesenchymal cells, the higher levels of asparagine they released.
St. Jude Children's Research Hospital
"Leukemic cells that resist asparaginase and survive in this protective niche of the bone marrow might be the reason that leukemia recurs in some children who have been treated with this drug," said Dario Campana, M.D., Ph.D., a member of the St. Jude Oncology and Pathology departments.
Campana is senior author of the report that appears in the online pre-publication issue of "The Journal of Clinical Investigation."
"Our findings indicate that the level of activity of the "ASNS" gene in the mesenchymal cells is key to protecting leukemic cells in the bone marrow from asparaginase," Campana said. "This insight will help researchers find ways to disrupt this safe haven for leukemic cells that need asparagine," added James R. Downing, M.D., St. Jude scientific director and chair of the Pathology department. Downing is a co-author of "The Journal of Clinical Investigation" paper. The "ASNS" gene controls production of the enzyme asparagine synthetase (ASNS), which leukemic cells use to make asparagine.
The study's findings also suggest that drugs now being developed to block ASNS should be tested to see if they also prevent mesenchymal cells from making this amino acid. In addition, the ability of mesenchymal cells to make asparagine might be decreased by cancer drugs that are already known to disrupt the activity of those cells.
"Because asparaginase is so widely used to treat ALL, this new insight into how mesenchymal cells protect leukemic cells is very important," said Ching-Hon Pui, M.D., chair of the Oncology department and American Cancer Society Professor at St. Jude. "The more we learn about the molecular interactions between these cells, the more likely we'll be able to enhance the anti-leukemic action of asparaginase and perhaps other anti-leukemic drugs as well," said Pui, a co-author of the paper. "That would reduce the recurrence rate of ALL and continue our successful efforts to increase the survival rate of ALL."
Previous research at St. Jude and elsewhere had shown that direct contact with bone marrow mesenchymal cells is essential for the long-term survival and multiplication of leukemic lymphoblasts. In the current study, the team found that the gene for ASNS was more than 20 times active in producing this enzyme in mesenchymal cells than in ALL cells.
Experiments performed by co-authors Shotaro Iwamoto, M.D., and Keichiro Mihara, postdoctoral fellows in Campana's laboratory, demonstrated that ALL cells from different patients became much more resistant to asparaginase when cultured on top of a layer of mesenchymal cells. In order to determine whether it was the high levels of asparagine released by mesenchymal cells that protected ALL cells from asparaginase, the St. Jude team repeated the experiment, but blocked the ability of mesenchymal cells to make the ASNS enzyme and produce asparagine. In this case, the protective effect of mesenchymal cells was eliminated. Conversely, when the researchers caused the ASNS gene to work overtime making asparagine, the ability of the mesenchymal cells layer to protect the ALL cells was significantly enhanced. The team also showed that the more actively "ASNS" genes produced ASNS in mesenchymal cells, the higher levels of asparagine they released.
St. Jude Children's Research Hospital
Leukemic Cells Current Events and Leukemic Cells News RSSMDC scientists show how hematopoietic stem cell development is regulated
During cell division, whether hematopoietic stem cells (HSCs) will develop into new stem cells (self-renewal) or differentiate into other blood cells depends on a chemical process called DNA methylation.
MGH study identifies first molecular steps to childhood leukemia
A Massachusetts General Hospital (MGH)-based research team has identified how a chromosomal abnormality known to be associated with acute lymphoblastic leukemia (ALL) - the most common cancer in children - initiates the disease process.
Mutant genes in high-risk childhood leukemias identified
A research team has pinpointed a new class of gene mutations, which identify cases of childhood acute lymphoblastic leukemia (ALL) that have a high risk of relapse and death.
A miR boost enables acute leukemia cells to mature
A new study by Ohio State University cancer researchers shows that boosting the level of a molecule called miR-29b in acute myeloid leukemia (AML) cells can reverse gene changes that trap the cells in an immature, fast growing state of development.
Gene mutation improves leukemia drug's effect
Gene mutations that make cells cancerous can sometimes also make them more sensitive to chemotherapy. A new study led by cancer researchers at Ohio State University shows that a mutation present in some cases of acute leukemia makes the disease more susceptible to high doses of a particular anticancer drug.
Arsenic-based therapy shown to help eradicate leukemia-initiating cells
In both leukemia and solid tumors, there exists among the multitude of warrior cancer cells a small subgroup that work undercover, patiently lying in wait to launch their attacks.
Two suppressor molecules affect 70 genes in leukemia
By restoring two small molecules that are often lost in chronic leukemia, researchers were able to block tumor growth in an animal model.
St. Jude identifies the specific cell that causes eye cancer, disproving long-held theory
Investigators at St. Jude Children's Research Hospital have identified the cell that gives rise to the eye cancer retinoblastoma, disproving a long-standing principle of nerve growth and development.
Novel strategy under study for aggressive leukemia
A novel strategy to hopefully beat into oblivion one of the most aggressive forms of acute myelogenous leukemia combines the strengths of some of the newest leukemia agents, researchers say.
St. Jude finds factors that accelerate resistance to targeted therapy in lymphoblastic leukemia
Results of a study by investigators at St. Jude Children's Research Hospital provide strong evidence for why the targeted therapy drug imatinib (Gleevec™), which has revolutionized the treatment of chronic myelogenous leukemia (CML), is often unable to prevent relapse of a particularly aggressive form of acute lymphoblastic leukemia (ALL).
More Leukemic Cells Current Events and Leukemic Cells News Articles
|
The Leukemic Cell (Methods in Haematology) by D. Catovsky (Editor) The quest for a better understanding of the leukaemic process has continued unabated since this book first came to light almost a decade ago. There have been major advances in technology and with it a more comprehensive view of the great heterogeneity of human leukaemias and a wider application of more precise diagnostic methods. The greatest progress has been in the fields of immunology, with the development of an ever-growing range of monoclonal antibodies specific for leucocyte differentiation and functional antigens, and of molecular genetics, with new and highly sophisticated tecniques. The advances in both areas have been nothing short of spectacular. For this reason we have included in this edition two chapters on cell markers and two on DNA analysis. As before, the methods are... | |
|
The Effect of Glucose Analogues on the Metabolism of Human Leukemic Cells by John & Bernard Landau & Kent Wight & Dean Burk Laszlo (Author) | |
|
Glucocorticoid Receptor Structure Leukemic Cell Responses (Molecular Biology Intelligence Unit) by Bahiru Gametchu (Author) This monograph brings the reader up to date on the basic therapeutic mechanism of glucocorticoid action in the treatment of various lymphoproliferative diseases, most notably in acute lymphoblastic leukemias. As a target protein, the structure and function of both the intracellular and plasma membrane-associated glucocorticoid receptors are reviewed. The various functional domains of the glucocorticoid receptor interaction with a variety of heat shock proteins, transcription factors and specific DNA sequences and how this leads to biological response are addressed. The book aims at leading not only to a better understanding of how glucocorticoid hormones impart their therapeutic effect, but also to the eventual development of efficient diagnostic tools for the identification of... | |
|
Hemopoietic colonies: In vitro cloning of normal and leukemic cells (Recent results in cancer research) by Donald Metcalf (Author) | |
|
Glucocorticoid Receptor Structure and Leukemic Cell Responses (Molecular Biology Intelligence Unit) by Bahiru Gametchu (Author) | |
|
Biochemical and Biophysical Research Communications. Volume 194. Pp. 811-1541. Spontaneous Nucleosomal DNA Fragmentation in Murine Leukemic L1210 Cells by Jiang et al. Etc. 1993 by Jiang et al (Author) | |
|
Hemopoietic colonies: In vitro cloning of normal and leukemic cells (Recent results in cancer research) by Donald Metcalf (Author) | |
|
Molecular mechanisms in human leukemic cell (HL-60) differentiation by Thelma Alicia Chen (Author) | |
|
Extracorporeal irradiation of the blood and lymph in the study of normal and leukemic cell proliferation (Brookhaven lecture series) by Eugene P Cronkite (Author) | |
|
Regulation of expression of c-myc proto-oncogene in the human promyelocytic leukemic cell line HL-60 by Zahra Salehi (Author) |
| © 2009 BrightSurf.com |