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Blood, 1 August 2006, Vol. 108, No. 3, pp. 1030-1036.
Prepublished online as a Blood First Edition Paper on April 6, 2006; DOI 10.1182/blood-2005-12-007005.
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NEOPLASIA
The Flt3 receptor tyrosine kinase collaborates with NUP98-HOX fusions in acute myeloid leukemia
Lars Palmqvist,
Bob Argiropoulos,
Nicolas Pineault,
Carolina Abramovich,
Laura M. Sly,
Gerald Krystal,
Adrian Wan, and
R. Keith Humphries
From the Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada; Institute of Laboratory Medicine, Sahlgrenska University Hospital, Göteborg, Sweden; and Departments of Pathology and Medicine, University of British Columbia, Vancouver, BC, Canada.
In leukemogenesis, several genetic changes conferring a proliferative and/or survival advantage to hematopoietic progenitor cells in addition to a block in differentiation are required. Here, we demonstrate that overexpression of the wild-type (wt) Flt3 receptor tyrosine kinase collaborates with NUP98-HOX fusions (NUP98-HOXA10 and NUP98-HOXD13) to induce aggressive acute myeloid leukemia (AML). We used a mouse transplantation model to show their synergism in cotransduced bone marrow cells as well as in a cellular model of leukemic progression. Furthermore, our data support the finding that Meis1 overexpression leads to marked elevation in Flt3 transcription and extend it to the context of NUP98-HOX–induced leukemia. Together, these results support a multistep model where the synergism between NUP98-HOX and wt-Flt3 is the result of the ability of Flt3 to increase proliferation of myeloid progenitors blocked in differentiation by NUP98-HOX fusions and reveal a direct role for wt-Flt3 in the pathobiology of AML. Given the similarities in the leukemogenic role of native HOX and NUP98-fused HOX genes, our results underscore the clinical significance of the recurrent co-overexpression of wt-FLT3 and HOX in human leukemia and suggest that specific FLT3 inhibitors could be useful in treatment of HOX-induced AML or acute lymphoblastic leukemia (ALL).
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