Enforced expression of an Flt3 internal tandem duplication in human CD34+ cells confers properties of self-renewal and enhanced erythropoiesis Journal Article
| Authors: | Chung, K. Y.; Morrone, G.; Schuringa, J. J.; Wong, B.; Dorn, D. C.; Moore, M. A. S. |
| Article Title: | Enforced expression of an Flt3 internal tandem duplication in human CD34+ cells confers properties of self-renewal and enhanced erythropoiesis |
| Abstract: | To investigate the role of constitutively active internal tandem duplication (ITD) mutants of the Fms-like tyrosine kinase 3 (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 cocultures, numerous early cobblestone areas (CAs) were generated within 10 to 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 signal transducer and activator of transcription 5 (Stat5) activation plays a major role in this phenotype, although additional downstream targets of W51 may be relevant. Flt3-ITD + acute myeloid leukemia (AML) blasts from patients invariably generated early AG1295-sensitive CAs in MS-5 cocultures, further validating the phenotype observed in transduced CD34+ cells. © 2005 by The American Society of Hematology. |
| Keywords: | signal transduction; controlled study; protein expression; unclassified drug; acute granulocytic leukemia; human cell; dna-binding proteins; proto-oncogene proteins; validation process; mutant protein; cell proliferation; phenotype; animals; mice; cells, cultured; cd34 antigen; proto-oncogene proteins c-kit; erythropoiesis; cell renewal; transduction, genetic; gene expression regulation; leukemogenesis; stem cells; umbilical cord blood; immunophenotyping; trans-activators; receptor protein-tyrosine kinases; flt3 ligand; stat5 protein; stat5 transcription factor; antigens, cd34; protein inhibitor; blast cell; tyrphostins; colony formation; fms-like tyrosine kinase 3; leukemia, myelocytic, acute; 6,7 dimethyl 2 phenylquinoxaline; pd 16; protein w51; milk proteins |
| Journal Title: | Blood |
| Volume: | 105 |
| Issue: | 1 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2005-01-01 |
| Start Page: | 77 |
| End Page: | 84 |
| Language: | English |
| DOI: | 10.1182/blood-2003-12-4445 |
| PUBMED: | 15242879 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 25" - "Export Date: 24 October 2012" - "CODEN: BLOOA" - "Source: Scopus" |
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