Targeting the Mechanism of Differentiation Arrest in a Novel Model of Acute Leukemia
Infant acute leukemias (arising in children less than one year old) makes up a unique subset of leukemias that are particularly lethal and that are characterized by recurrent mutations in one gene. This gene has been termed the mixed lineage leukemia (or MLL) gene, and mutations in MLL are found in the majority of infant leukemias as well as in smaller proportions of childhood and adult leukemias. The mutations in MLL are intriguing, because they are the result of chromosomal breakage which abnormally joins the MLL gene to a variety of partner genes. These mutant "fusion" genes disrupt normal blood development, and lead to immature cells which no longer respect normal bone marrow regulation. This lack of respect for normal development eventually results in leukemia as these immature cells accumulate in the bone marrow and the blood.
Despite the multiple partners of MLL, they all seem to act by increasing the level of another gene termed HoxA9. HoxA9 is a critical gene during development, but needs to be turned off as cells mature. MLL-partners prevent HoxA9 from being switched off. HoxA9 thus appears to be a common pathway in the development of leukemia, and an attractive target for drug development. We have developed a new leukemia cell line with a built-in reporter such that the cells turn fluorescently green when the HoxA9 pathway is inhibited. These cells will allow us to understand how HoxA9 is working, and will allow us to identify drugs which turn off the HoxA9 pathway. Hopefully these anti-HoxA9 and anti-MLL-based drugs will be useful in the treatment of infant leukemia.
2013 Project Update
Even with advances in our understanding of AML, it remains a devastating disease in both children and adults. Even those patients who are cured of their leukemia suffer from the long-term side-effects of the medications used to cure the disease. AML is currently treated with chemotherapy, and it is remarkable to note that we are using the same chemotherapy drugs that were developed more than thirty years ago. We need new and more effective drugs for the treatment of this disease.
Despite these sobering facts, there exists one dramatic treatment success story. There is a subset of AML called acute promyelocytic leukemia (APL) that makes up 10% of cases, though has a cure rate of more than 90%. This remarkable success is due to drugs that can trigger the maturation of the APL cells. Instead of trying to kill these leukemic cells, we can trick them into resuming their normal process of maturation and death. Unfortunately, this maturation or differentiation therapy is not available for the vast majority of patients with other forms of AML.
With the goal of identifying new differentiation therapies, we first needed to develop a model system of acute myeloid leukemia in which we could easily and reliably monitor the maturational status of the cells. We accomplished this by engineering a cell line model from the bone marrow cells of a transgenic mouse in which the cells become green fluorescent upon maturation.
The development of this novel cell line permitted the large-scale screen of more than 330,000 chemical compounds. In this screen, we asked a simple question, "which compounds can trigger maturation, and therefore make these cells turn green fluorescent?" From this large library of compounds, we have narrowed the list to thirteen confirmed and active drugs.
At this point, these compounds need to be chemically modified to increase their potency and to ensure that they can be given to both animals and humans with maximum anti-leukemia effect and minimal non-specific toxicity. We are excited by the possibility that one of these compounds may represent a new, and sorely needed, treatment for acute myeloid leukemia.