Paper of the Month: An integrated approach of functional genomic screens in leukemia patients
"This paper was selected because it describes an important discovery by the Tyner research team that has led to the identification of a very promising chemotherapeutic strategy that offers greater precision and improved success for targeting childhood and adult B lymphocyte malignancies."
- Mary Stenzel-Poore, Ph.D.
Senior Associate Dean for Research
Each year in the United States, approximately 3,500 children will be diagnosed with leukemia; three out of four of these patients will have acute lymphoblastic leukemia (ALL)— a type of cancer of the blood and bone marrow. This makes ALL the most common cancer in children, accounting for one-quarter of all childhood malignancies for children under ten.
"ALL is a highly aggressive disease and requires immediate therapeutic intervention," said Jeffrey Tyner, Ph.D., an assistant professor in the department of Cell & Developmental Biology. "To optimize therapeutic effectiveness, patients are risk-stratified into disease subsets based upon broad genetic differences such as chromosomal translocations, deletions and duplications. However, the genetic etiology of disease in most of these leukemic subsets remains unclear, and most therapeutic strategies involve non-targeted chemotherapeutic agents."
Most patients with ALL are given induction chemotherapy, which achieves a remission in more than 95% of children. Side effects include a wide variety of short-term problems such as cardiac dysfunction and immunosuppression and may also include long-term, late effects such as delayed growth and cognitive development as well as increased risk of secondary malignancy. The development of more targeted agents that could improve outcomes and reduce side-effects, however, requires a detailed understanding of the cancer causing genes in each patient as well as the biochemical mechanisms linking each cancer-causing gene with malignancy.
Researchers in Jeffrey Tyner's laboratory at the OHSU Knight Cancer Institute are working to identify cancer-causing genes in leukemia patients by using an integrated approach of functional genomic screens. Results from research using this approach have demonstrated that specimens of the t(1;19) subtype (meaning the leukemia contains a translocation between chromosomes 1 and 19) are uniquely sensitive to silencing of a cell surface receptor called ROR1.
In determining the underlying genetic factors that cause these t(1;19) patient specimens to exhibit sensitivity to ROR1 loss, the team recently made an exciting discovery. "We found that all specimens from patients diagnosed with the t(1;19) ALL subtype produced large amounts of the ROR1 protein compared with other types of leukemia," said Vincent Bicocca, Ph.D., a postdoc in the Institute of Molecular Biology at the University of Oregon. "Continued analysis revealed that t(1;19) ALL cells are also dependent upon expression and signaling of the pre-B-cell receptor signaling complex (preBCR), and further that the signaling pathways downstream of ROR1 and the preBCR are capable of functionally interacting."
In characterizing the signaling interaction between ROR1 and the preBCR, the Tyner Team discovered that direct targeting of the preBCR with a small molecule inhibitor (dasatinib) resulted in partial killing of t(1;19) ALL cells. "However, inhibiting the preBCR with dasatinib also resulted in increased pro-survival signaling from ROR1, suggesting a mechanism for therapeutic evasion and a potential means for disease relapse during treatment," said Dr. Bicocca.
To further investigate this possibility, the investigators simultaneously inhibited both ROR1 and the preBCR and observed an increased killing capacity with this combination treatment. They showed that conclusions drawn from t(1;19) ALL could be applied to other acute leukemias sharing the characteristic of ROR1 overexpression and preBCR signaling.
The team's findings were recently published in Cancer Cell, in a paper titled, Crosstalk between ROR1 and the Pre-B Cell Receptor Promotes Survival of t(1;19) Acute Lymphoblastic Leukemia.
"These results have immediate clinical impact," said Dr. Tyner, "as they show that the small molecule inhibitor, dasatinib, specifically targets and kills acute leukemias that express the preBCR. Our study also demonstrates that direct targeting of ROR1 is a viable therapeutic strategy, and simultaneous treatment with dasatinib and a ROR1-targeted drug would be the most effective therapeutic strategy."
In addition to the clinical significance of this work, the research conducted in this paper contributes to the team's understanding of the poorly characterized protein ROR1, and highlights an important role for ROR1 in normal B-cell development. Dr. Tyner said, "Continued work will be required to fully understand the function and mechanism of action of ROR1 in ALL as well as the best strategy for targeting ROR1 for therapeutic intervention."
Pictured above: (top) Jeffrey Tyner, Ph.D.; (bottom) Vincent Bicocca, Ph.D.
Vincent Bicocca, Ph.D.
Bill Chang M.D., Ph.D.
Behzad Kharabi Masouleh, M.D.
Markus Muschen, M.D., Ph.D.
Marc Loriaux, M.D., Ph.D.
Brian Druker, M.D.
Jeffrey Tyner, Ph.D.
ABOUT THE PAPER OF THE MONTH
The School of Medicine newsletter spotlights a recently published faculty research paper in each issue. The goals are to highlight the great research happening at OHSU and to share this information across departments, institutes and disciplines. The monthly paper summary is selected by Associate Dean for Basic Science Mary Stenzel-Poore, Ph.D., and Associate Dean for Clinical Science Eric Orwoll, M.D.
More Published Papers
The entire list of OHSU papers published this month is here.