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 Blood, 1 January 2005, Vol. 105, No. 1, pp. 77-84.
Prepublished online as a Blood First Edition Paper on July 8, 2004; DOI 10.1182/blood-2003-12-4445.

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Submitted January 5, 2004
Accepted June 10, 2004

Enforced expression of a Flt3 internal tandem duplication in human CD34+ cells confers properties of self-renewal and enhanced erythropoiesis

Ki Y Chung, Giovanni Morrone, Jan J Schuringa, Bryan Wong, David C Dorn, and Malcolm A Moore*

Laboratory of Developmental Hematopoiesis, Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
Laboratory of Developmental Hematopoiesis, Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; Department of Experimental and Clinical Medicine, University Of Catanzaro, Catanzaro, Italy

* Corresponding author; email: m-moore{at}ski.mskcc.org.

To investigate the role of constitutively active internal tandem duplication (ITD) mutants of the Flt3 receptor in leukemogenesis, we introduced the Flt3-ITD, W51, into human cord-blood CD34+ cells and evaluated their phenotype in diverse hematopoietic assays. W51 expression resulted in a strong proliferative advantage and enhanced erythropoiesis as determined by immunophenotyping, colony assays and molecular analyses. In MS-5 stromal co-cultures, numerous early cobblestone areas (CAs) were generated within 10-14 days. Such W51-associated early CAs disappeared by 4 weeks, yet retained self-renewal properties as demonstrated by generation of secondary and tertiary CAs upon replating. This phenotype appears related to the expression of W51 since it was abolished by exposure to the FLT3 inhibitor, AG1295, but not to the c-kit inhibitor PD16. Wild-type Flt3 overexpressing CD34+ cells exposed to high levels of its physiologic ligand, did not produce early CAs, highlighting differences in intracellular signaling between wild-type Flt3 and W51. W51-associated Stat5 activation plays a major role in this phenotype, although additional downstream targets of W51 may be relevant. Flt3-ITD+ AML blasts from patients invariably generated early AG1295-sensitive CAs in MS-5 co-cultures, further validating the phenotype observed in transduced CD34+ cells.


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