1. ¹Division of Hematology/Oncology, Children's Hospital, Boston, MA, USA;
2. ²Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, MA, USA
3. ³Harvard Medical School, Boston, MA, USA

Correspondence: Dr SA Armstrong, Division of Hematology/Oncology, Children's Hospital, Karp Family Research Laboratories, 1 Blackfan Circle, Boston, MA 02215, USA. E-mail: Scott.Armstrong@childrens.harvard.edu

⁴These authors contributed equally to this work

Received 7 January 2007; Revised 6 August 2007; Accepted 7 August 2007; Published online 13 September 2007.

Abstract

Human leukemias harboring chromosomal translocations involving the mixed lineage leukemia (MLL, HRX, ALL-1) gene possess high-level expression, and frequent activating mutations of the receptor tyrosine kinase FLT3. We used a murine bone marrow transplant model to assess cooperation between MLL translocation and FLT3 activation. We demonstrate that MLL-AF9 expression induces acute myelogenous leukemia (AML) in approximately 70 days, whereas the combination of MLL-AF9 and FLT3-ITD does so in less than 30 days. Secondary transplantation of splenic cells from diseased mice established that leukemia stem cells are present at a very high frequency of approximately 1:100 in both diseases. Importantly, prospectively isolated granulocyte macrophage progenitors (GMPs) coinfected with MLL-AF9 and FLT3-ITD give rise to a similar AML, with shorter latency than from GMP transduced with MLL-AF9 alone. Cooperation between MLL-AF9 and FLT3-ITD was further verified by real-time assessment of leukemogenesis using noninvasive bioluminescence imaging. We used this model to demonstrate that MLL-AF9/FLT3-ITD-induced leukemias are sensitive to FLT3 inhibition in a 2–3 week in vivo assay. These data show that activated FLT3 cooperates with MLL-AF9 to accelerate onset of an AML from whole bone marrow as well as a committed hematopoietic progenitor, and provide a new genetically defined model system that should prove useful for rapid assessment of potential therapeutics in vivo.