Acute myeloid leukemia (AML) in adults is a devastating disease with a 5-year survival rate of only 25%. New treatments for AML are lacking, and the current standard of care for chemotherapy has not changed in the last thirty years. One success story in the treatment of AML has been the development of therapies which promote the maturation, or differentiation of the leukemic cells. In the small subset (~10%) of AML patients with acute promyelocytic leukemia (APL), differentiation therapy in the form of all-trans retinoic acid (ATRA) and arsenic are both well-tolerated and extremely effective, leading to 5-year survival rates approaching 80%. Unfortunately, differentiation therapy is not available for the remaining 90% of acute myeloid leukemia patients. The homeobox protein HoxA9 is expressed in early hematopoiesis and is critical to the normal development of cells along the myeloid lineage. The inappropriate expression of HoxA9 has been demonstrated in approximately 70% of AML. Furthermore, the subset of leukemias which express a fusion oncoprotein involving the MLL (mixed lineage leukemia) gene are dependent upon the expression of HoxA9. These observations make HoxA9 and its downstream targets attractive candidates for inhibition by small molecule probes. Research has been hindered by inadequate model systems of leukemia and the limited availability of primary patient samples. A novel in vitro model of AML has been developed whereby primary murine myeloid cells are arrested in an immature state by the oncoprotein HoxA9. These cells allow for the identification of biologically relevant compounds that can overcome myeloid differentiation arrest. Two types of molecules can be identified: those that directly interfere with the mechanism of differentiation arrest established by HoxA9, and those that are capable of promoting differentiation in a HoxA9-independent manner. The assay cell line is engineered with a built-in marker of differentiation as it expresses the green fluorescent protein (GFP) from a promoter which is active only in mature cells. Thus, compounds that promote differentiation can be readily identified in a high-throughput fashion by assaying cells for green fluorescence. Secondary and counterscreen assays will eliminate potentially autofluorescent compounds and will confirm the effect on myeloid differentiation by assaying for changes in gene expression and cell surface marker expression. The development of a small molecule capable of promoting differentiation in acute myeloid leukemia will be an important advancement in the current state of leukemia chemotherapy. Page 1 of 1
Acute myeloid leukemia (AML) is a devastating disease and new treatments for AML are in desperate need. Traditional chemotherapy, which typically poisons rapidly dividing leukemia cells, is ultimately ineffective in 75% of cases. A novel model system of AML has been devised to identify novel compounds which trigger leukemic cells to resume the normal process of maturation, thereby losing their proliferative and leukemic potential. Page 1 of 1
| Lewis, Timothy A; Sykes, David B; Law, Jason M et al. (2016) Development of ML390: A Human DHODH Inhibitor That Induces Differentiation in Acute Myeloid Leukemia. ACS Med Chem Lett 7:1112-1117 |
| Sykes, David B; Kfoury, Youmna S; Mercier, François E et al. (2016) Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia. Cell 167:171-186.e15 |
