ATLANTA, Dec. 11 /PRNewswire/ -- Three studies presented today at the 47th Annual Meeting of the American Society of Hematology suggest that new therapeutic approaches are powerful and effective tools for treating blood-borne and bone marrow-related diseases. The studies examine a critical cancer-producing gene known as BCL6, a gene known as MCL-1 that interferes with agents killing cancer cells, and a genetic modification of autologous stem cell transplantation.
“Genetic approaches have the potential to change everything in terms of how we think about disease and approach treatments,” said Katherine A. High, M.D., Howard Hughes Medical Institute, Philadelphia, Penn. “This type of research will lead to the development of therapies for some of the most complex diseases we are fighting.”
BCL6 Attenuates DNA Damage Sensing in Normal and Malignant B-Cells by Directly Repressing ATR [Abstract 157]
In order to produce high affinity antibodies, B-lymphocytes (B-cells) must undergo a remarkable process whereby they form structures known as germinal centers, during which they divide rapidly while mutating their immunoglobulin genes. The BCL6 (B-Cell-Lymphoma-6) protein is required for B-cells to enter this “germinal center phase” and can cause these cells to transform into malignant tumors. Germinal centers are the site of antibody production within the periphery of lymph nodes and are populated mostly by B-cells.
To characterize the mechanism through which BCL6 mediates these actions, researchers at the Albert Einstein College of Medicine’s Department of Developmental and Molecular Biology identified BCL6 target genes and observed that a number of them are critical regulators of DNA damage-sensing checkpoints, including the ATR (ataxia telangiectasia and Rad-3-related) protein. ATR plays a critical role in sensing when DNA becomes mutated in cells and triggers a downstream response, whereby cells stop dividing and repair the damage, or undergo cell death if damage is extensive.
Researchers found that a major role of BCL6 in germinal center formation is to block cellular response to DNA damage by suppressing the activity of ATR. This allows B-cells to ignore and survive the DNA damage that occurs as a byproduct of producing high affinity antibodies. The same mechanism also seems to be required for disease progression, since it was observed that BCL6 could induce abnormal survival and genomic instability properties in mature B- cells.
Because of this, scientists wondered whether blocking the activity of BCL6 would reactivate ATR and restore DNA damage sensing. If so, this could powerfully enhance the activity of chemotherapy agents commonly used to treat lymphomas, and lead to more effective and less toxic therapeutic regimens. Accordingly, the researchers found that blocking BCL6 with specific inhibitors could kill lymphoma cells and synergize with DNA damaging agents, including radiation and chemotherapy treatments.
“This double-pronged approach to treating B-cell lymphomas holds great promise for improving the treatment of patients suffering from this condition,” said Stella Maris Ranuncolo, M.D., Ph.D., Albert Einstein College of Medicine of Yeshiva University, Chanin Institute for Cancer Research, Bronx, N.Y. “This work links critical events in the normal immune system with the development of cancer, and shows how specific molecular targeted therapeutics can be designed to re-program tumor cells to undergo cell death with minimal impact on the host.”
A Gene Expression Connectivity Map Identifies Rapamycin as a Glucocorticord Resistance Reversal Agent in Lymphoblastic Leukemia [Abstract 108]
Glucocorticoids (GC) -- hormones normally released from the adrenal glands that are also used as therapeutics -- are vital in the treatment of acute lymphoblastic leukemia (ALL), a quickly progressing disease in which too many immature white blood cells are found in the blood and bone marrow. Patients whose ALL cells are resistant to GC-induced killing of leukemia cells have a much worse prognosis than patients whose cells are sensitive to GCs. Unfortunately, strategies to pharmacologically overcome drug resistance in general, and GC resistance in particular, are lacking.
Researchers at Children’s Hospital and the Broad Institute in Boston wanted to know if profiles of gene activity found in cancer cells could be compared to gene expression profiles associated with potential new drug treatments by systematically performing gene expression analyses on cells treated with FDA-approved drugs. This is known as the “Connectivity Map.”
As a pilot for the Connectivity Map concept, researchers profiled approximately 300 treatments and, when compared with pre-treatment bone marrow from patients with GC-sensitive or resistant ALL, noticed the gene expression profiles associated with the drug rapamycin matched that of GC sensitivity.
Rapamycin -- used to help prevent the body from rejecting organ and bone marrow transplants by inducing programmed cell death (i.e., an apoptotic effect) -- is thought to inhibit the activity of the protein mTOR (mammalian target of rapamycin), which promotes tumor growth.
Rapamycin treatment of ALL cells allowed GCs to kill ALL cells at a much lower dose, showing that rapamycin is able to reverse GC resistance. To determine how rapamycin reversed GC resistance in ALL cells, researchers examined the components of the GC resistance profile and noted an over- expression of the anti-apoptotic gene MCL-1. The presence of MCL-1 decreased in rapamycin-treated cells, whereas the existence of other anti-apoptotic molecules was unaffected. This suggests that a decrease in MCL-1 expression is necessary for the rapamycin-mediated increase in GC sensitivity.
“The ability to computationally connect gene expression profiles of disease states and therapeutics is an important tool to help expedite the discovery of new combination therapies,” said Scott A. Armstrong, M.D., Ph.D., Children’s Hospital and Dana-Farber Cancer Institute, Boston, Mass. “The Connectivity Map represents a novel approach for the identification of promising combination therapies for cancer.”
Todd Golub, M.D., Cancer Program, Broad Institute in Cambridge and co-author on this study, noted, “Based on these and other results, we believe a publicly accessible database containing profiles associated with all FDA-approved drugs is warranted and may help us target appropriate drug treatments to the appropriate patients in the future.”
Long-Term Follow-Up of Patients Treated by Gene Therapy for X-linked Chronic Granulomatous Disease [Abstract 194]
The human immune system, which defends the body against infection and disease, is made up of a complex network of cells and organs. When any part of this system is faulty, it interrupts immune response and results in an immunologic disorder. Chronic granulomatous disease (CGD) is a group of rare, inherited immulogic disorders that are caused by defects in the immune system cells, called phagocytes.
Although CGD can be cured by stem cell transplantation, this approach is usually limited only to patients with identically matched donors, as mismatched transplantation is risky and can be fatal. A therapeutic alternative for CGD patients is the transplantation of genetically modified autologous hematopoietic stem cells (HSCs) -- stem cells from a patient’s own blood, bone marrow, or tissue.
In January 2004, researchers at University Hospital in Frankfurt, Germany, initiated a phase I/II clinical trial for CGD patients which included conditioning with busulfan prior to infusion of genetically modified HSCs. Busulfan is a type of chemotherapy that interferes with the growth of cancer cells, slowing their growth and spread in the body.
Approximately 14 months after the stem cell transplant, therapeutically significant gene marking levels were detected in white blood cells defending the body against bacteria and viruses, with phagocytes as much as 60 percent functionally corrected. Additionally, bone marrow gene marking was detected at levels between 30 and 40 percent at one year after transplantation of gene modified cells. While normal levels for a healthy subject is 100 percent, researchers were pleased with the higher than expected results, as this was the first study in which corrected cells were detected long-term in a sufficient and functional manner.
“Using a person’s own stem cells may be an effective treatment choice for chronic granulomatous disease and provides an option beyond the potentially life-and-death decision of stem cell transplants,” said Marion G. Ott, M.D., University Hospital, Frankfurt, Germany. “Moreover, using therapeutic materials from one’s own body eliminates the need to find perfect transplant matches between different people.”
The American Society of Hematology (www.hematology.org) is the world’s largest professional society concerned with the causes and treatment of blood disorders. Its mission is to further the understanding, diagnosis, treatment, and prevention of disorders affecting blood, bone marrow, and the immunologic, hemostatic, and vascular systems, by promoting research, clinical care, education, training, and advocacy in hematology.
The American Society of Hematology
CONTACT: Leslie Priest, Spectrum Science Communications, +1-202-955-6222,lpriest@spectrumscience.com; Aislinn Raedy, American Society of Hematology,+1-202-776-0544, araedy@hematology.org, or On-site (12/9-12/13),+1-404-222-5705
Web site: http://www.hematology.org/