Scott Armstrong

Department of Genetics
Children's Hospital/Dana Farber Cancer Institute
New Research Building, Room 8211
1 Blackfan Circle
Boston. MA 02115
Tel: (617) 919-2508
Fax: (617) 730-0934
Email: scott_armstrong@dfci.harvard.edu

We are using genomic approaches to characterize human leukemia, while developing murine models to test hypotheses generated by these studies. We recently demonstrated that acute lymphoblastic leukemias with rearrangement of the MLL gene on chromosome 11q23 (MLL) have a highly distinct gene expression pattern as compared to other acute lymphoblastic leukemias (ALL). Based on these data, we hypothesize that the difference in gene expression is the reason for the poor response to standard ALL therapy. Also, we feel that the dramatic difference in gene expression is due to this leukemia arising from a different cell of origin. Of particular interest was the fact that the gene that best distinguished MLL from other acute leukemias was FLT3. We have subsequently shown that FLT3 is constitutively active in MLL, and that a small molecule inhibitor of FLT3 is active against the disease in vivo. More recently we have extended these observations to show that 20% of children with ALL whose disease will ultimately relapse, have leukemia harboring a FLT3 mutation. These discoveries have led to the development of a clinical trial assessing FLT3 inhibitors in relapsed acute leukemia.

Our current research aims to build upon these discoveries. We are developing two approaches that will address both fundamental mechanisms of leukemogenesis, and the application of kinase inhibitors to leukemia therapy. We are generating mouse models of MLL rearranged leukemia that should be useful for both understanding mechanisms of MLL-induced leukemogenesis, and for testing new therapeutics. With these models we will determine the mechanisms behind the abnormal cell fate decision and self-renewal program induced by leukemogenic fusion proteins. This should also allow us to characterize the cell of origin of MLL rearranged leukemias in great detail. Similarly we will attempt to understand the genetic cooperation between MLL rearrangements and FLT3 mutations. We are also involved in the biological questions that will be addressed in the FLT3 inhibitor trial. These fundamental studies, along with the ongoing clinical trial with FLT3 inhibitors, provide an excellent opportunity to improve upon current therapies for patients with leukemia.

References:

• Armstrong, S.A., Staunton, J.E., Silverman, L.B., Pieters, R., den Boer, M.L., Minden, M.D., Sallan, S.E., Lander, E.S., Golub, T.R. and Korsmeyer, S.J. MLL translocations specify a distinct gene expression profile, distinguishing a unique leukemia. Nature Genetics 2002; 30:41-47; published online: Dec. 3, 2001, DOI: 10.1038/ng765.
• Armstrong, S.A., Kung, A.L., Mabon, M.E., Silverman, L.B., Stam, R.W., den Boer, M.L., Pieters, R., Sallan, S.E., Kersey, J.H., Fletcher, J.A., Golub, T.R., Griffin, J.D., Korsmeyer, S.J. Inhibition of FLT3 in MLL: Validation of a therapeutic target identified by gene expression based classification. Cancer Cell 2003; 3: 173-183.
• Armstrong, S.A., Look A.T. Molecular genetics of acute lymphoblastic leukemia. J Clin Oncol 2005; 23(26):6306-15.
• Andrei V. Krivtsov, David Twomey, Zhaohui Feng, Matthew C. Stubbs, Yingzi Wang, Joerg Faber,Jason E. Levine, Jing Wang, William C. Hahn, D. Gary Gilliland, Todd R. Golub, & Scott A. Armstrong. MLL-AF9 transforms committed progenitors to leukemia stem cells by activation of a stem cell program. Submitted.