Since the early 1990’s, Dr. Jon Aster has been interested in the molecular biology of cancers of the blood and blood-forming elements, including leukemia and lymphoma. His laboratory conducts research on Notch, a fundamental signaling pathway that controls the way cells communicate with one another and respond to their external environment. This pathway plays a central role in regulating many aspects of normal cellular development. It is also important in certain forms of leukemia, most notably T-cell acute lymphoblastic leukemia (T-ALL). Newly made Notch receptors reside on the surface of the cell, but when activated by ligand proteins expressed on adjacent cells, part of the receptor moves to the nucleus where it activates gene expression. Notch is one of a handful of signaling pathways that permit cells to respond to cues from their environment. These instructive signals regulate normal behavior and often go awry in cancer and other diseases. Dr. Aster’s laboratory published a seminal paper in the journal Science in 2004 that described the discovery of mutations in the Notch1 receptor in T-ALL. These mutations increase Notch signaling and drive the growth of the leukemia cells. To date, this finding remains the best example of an abnormality in the Notch pathway that leads to a human cancer.
Jon Aster
FEATURED INVESTIGATOR
JON ASTER, MD PHD
Background
Hailing from the Midwest, Dr. Aster attended undergraduate school at the University of Michigan in Ann Arbor. He continued his postgraduate studies at the University of Michigan School of Medicine, where in 1987 he received a medical degree as well as a Ph.D. in human genetics. “While I was in medical school I really became attracted to pathology based on my perception that this field offered a great opportunity to couple clinical and research interests. When I asked the chairman of the department of pathology at Michigan, Dr. Peter Ward, ‘what is the best pathology department in the United States?’ he told me without question that it was Ramzi Cotran’s program at Brigham and Women’s Hospital. I rotated through the pathology department as a medical student in the fall of 1986 and was fortunate enough to gain entry to the program. I’ve never looked back.”
In the fall of 1987, Dr. Aster became a resident in pathology under the noted Dr. Cotran. He completed his fellowship in hematopathology in 1990, and three years later a fellowship in molecular oncology. He was named an assistant professor of pathology at the Harvard Medical School in 1996 and in 2000 was promoted to associate professor. In addition to numerous publications, professional honors, and hospital appointments, Dr. Aster is a co-leader of the Cancer Research Center of the Brigham Biomedical Research Institute, Deputy Director for Membership of the Dana Farber/Harvard Cancer Center, and leads the multi-institutional program project grant on oncogenic notch signaling, which is supported by the National Cancer Institute (NCI).
Research
Hailing from the Midwest, Dr. Aster attended undergraduate school at the University of Michigan in Ann Arbor. He continued his postgraduate studies at the University of Michigan School of Medicine, where in 1987 he received a medical degree as well as a Ph.D. in human genetics. “While I was in medical school I really became attracted to pathology based on my perception that this field offered a great opportunity to couple clinical and research interests. When I asked the chairman of the department of pathology at Michigan, Dr. Peter Ward, ‘what is the best pathology department in the United States?’ he told me without question that it was Ramzi Cotran’s program at Brigham and Women’s Hospital. I rotated through the pathology department as a medical student in the fall of 1986 and was fortunate enough to gain entry to the program. I’ve never looked back.”
In the fall of 1987, Dr. Aster became a resident in pathology under the noted Dr. Cotran. He completed his fellowship in hematopathology in 1990, and three years later a fellowship in molecular oncology. He was named an assistant professor of pathology at the Harvard Medical School in 1996 and in 2000 was promoted to associate professor. In addition to numerous publications, professional honors, and hospital appointments, Dr. Aster is a co-leader of the Cancer Research Center of the Brigham Biomedical Research Institute, Deputy Director for Membership of the Dana Farber/Harvard Cancer Center, and leads the multi-institutional program project grant on oncogenic notch signaling, which is supported by the National Cancer Institute (NCI).
Laboratory
Dr. Aster is working with three colleagues who are KO-8 recipients (an award that partners scientists-in-training with mentors). In addition to other funding from the NCI, Dr. Aster’s lab receives some support from private pharmaceutical concerns.
Collaborations
Among his many important research associations, Dr. Aster has an especially close collaboration with Dr. Stephen Blacklow of Brigham and Women’s Hospital. Dr. Blacklow is conducting an independent line of research focused on using structural biology to understand Notch function and to develop new specific inhibitors of the Notch pathway. Warren Pear, a Brigham-trained pathologist now working at the University of Pennsylvania in Philadelphia, is another important collaborator. Dr. Aster also heads an NCI-funded Notch program project grant centered on the role of Notch signaling in lymphocyte development and leukemia, in which Drs. Pear and Blacklow serve as coinvestigators.
Importance of Being at the Brigham
Dr. Aster has indicated that there is a tremendous added value to being a member of a department with a very strong commitment to research that is located within an institution providing world-class care to patients. The department of pathology at Brigham and Women’s Hospital has always had a strong research focus, first fostered by Dr. Cotran and subsequently maintained by his successor, Dr. Michael Gimbrone. This, in turn, has attracted many outstanding residents and fellows with strong research interests of their own. Among the several talented trainees who have passed through Dr. Aster’s laboratory are Andrew Weng, M.D., Ph.D., (now at the British Columbia Cancer Agency) and Chris French, M.D. Both of these individuals made innovative and important contributions to cancer research during their time at Brigham and Women’s Hospital.
Future
“We are actively developing humanized antibodies against the extracellular portion of Notch receptors, which we believe will provide a way to turn these receptors on and off at will.” Because Notch receptors control so many different aspects of cellular development, the ability to harness the pathway could prove to be very valuable in many areas of medicine, such as stem cell biology and tissue engineering. “While my lab is currently studying the effects of turning off Notch in cancer, Notch controls many normal and disease processes, such as wound healing, the development and function of blood vessels, and certain aspects of the immune response. We hope our work and that of our colleagues will provide opportunities to intervene in other disease processes involving Notch, including heart disease and diseases of immunity.”
Selected References
Weng AP, Nam Y, Wolfe MS, Pear WS, Griffin JD, Blacklow SC, Aster JC. Growth suppression of pre-T acute lymphoblastic leukemia cells by inhibition of Notch signaling. Mol Cell Biol 2003;23:655-664.
Weng AP, Ferrando AA, Lee W, Morris JP 4th, Silverman LB, Sanchez-Irizzarry SC, Look AT, Aster JC. Activating mutations of NOTCH1 in T cell acute lymphoblastic leukemia. Science 2004;306:269-271.
Chiang M, Xu ML, Histen G, Shestova O, Roy M, Nam Y, Blacklow SC, Sacks DB, Pear WS, Aster JC.Identification of a negative regulatory sequence that influences the leukemogenic activity of NOTCH1. Mol Cell Biol 2006;26:6261-6271.
Weng AP, Millholland JM, Yashiro-Ohtani Y, Arcangeli ML, Lau A, Wai C, Del Bianco C, Rodriguez CG, Sai H, Tobias J, Li Y, Wolfe MS, Shachaf C, Felsher D, Blacklow SC, Pear WS, Aster JC. c-Myc is an important direct target of Notch1 in T cell acute lymphoblastic leukemia/lymphoma. Genes Dev 2006;20:2096-2109.