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Blood, 15 July 2005, Vol. 106, No. 2, pp. 673-680.
Prepublished online as a Blood First Edition Paper on March 29, 2005; DOI 10.1182/blood-2004-05-1902.
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NEOPLASIA
Internal tandem duplications of the FLT3 gene are present in leukemia stem cells
Mark Levis,
Kathleen M. Murphy,
Rosalyn Pham,
Kyu-Tae Kim,
Adam Stine,
Li Li,
Ian McNiece,
B. Douglas Smith, and
Donald Small
From the Departments of Oncology, Pathology, and Pediatrics, Kimmel Cancer Center at Johns Hopkins, Baltimore, MD.
Internal tandem duplication mutations of the FLT3 gene (FLT3/ITD mutations) are the most frequent molecular abnormality in acute myeloid leukemia (AML) and are associated with a poor overall survival. While the normal FLT3 receptor is expressed in early hematopoietic progenitor cells, it has not been determined whether FLT3 mutations are present in the leukemic stem cells. In this study, we sorted primary AML samples into stem cell-enriched CD34+/CD38- fractions and then analyzed the sorted and unsorted cells for the FLT3 mutant-wild-type ratio. In each case, the FLT3 mutant-wild-type ratio was not changed by selection of CD34+/CD38- cells, implying that the mutations are present in the leukemic stem cells. We used the stem cell-enriched fraction to engraft nonobese diabetic-severe combined immunodeficient (NOD-SCID) mice and then confirmed that the FLT3/ITD mutation was present in the resultant engrafted marrow. As a final test of the importance of FLT3/ITD signaling in this engraftment model, we used a small molecule FLT3 inhibitor, CEP-701, to inhibit engraftment of FLT3/ITD stem cells. Taken together, these experiments establish that the FLT3/ITD mutations are present in leukemia stem cells, and that FLT3 inhibitors may have activity against these cells. (Blood. 2005;106:673-680)
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