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FLT3/ITD expression increases expansion, survival and entry into cell cycle of human haematopoietic stem/progenitor cells
Author(s) -
Li Li,
Piloto Obdulio,
Kim KyuTae,
Ye Zhaohui,
Nguyen Ho Bao,
Yu Xiaobing,
Levis Mark,
Cheng Linzhao,
Small Donald
Publication year - 2007
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2007.06525.x
Subject(s) - haematopoiesis , progenitor cell , stem cell , biology , cd34 , cancer research , fms like tyrosine kinase 3 , microbiology and biotechnology , mutation , genetics , gene
Summary Activating mutation of FLT3 by internal tandem duplications (ITDs) in the juxtamembrane region is the most common molecular aberration found in acute myeloid leukaemia (AML). In this study, a lentiviral vector containing two promoters achieved consistent and efficient co‐expression of FLT3/ITD and GFP in transduced human CD34 + haematopoietic stem/progenitor cells (HSPCs). When cultured in medium containing stem cell factor, thrombopoietin and FLT3 ligand (FL), FLT3/ITD‐transduced cells demonstrated enhanced self‐renewal and survival potential, unaffected by the withdrawal of FL. These cells retained a CD34 + CD38 −/dim immunophenotype, typical of HSPCs. Compared to cells transduced with a vector expressing GFP alone, FLT3/ITD‐transduced HSPCs had a higher fraction of cells in active cell cycle. FLT3/ITD‐transduced HSPCs were more sensitive to the induction of cytotoxicity by CEP‐701, a selective FLT3 inhibitor, indicating a rapid ‘addiction’ to signalling through this oncogenic pathway. The FLT3/ITD‐transduced HSPCs showed increased expression of Pim‐1, c‐Myc and Cyclin D3 (CCND3), each of which may contribute to the altered genetic programme instituted by FLT3/ITD signalling. Taken together, these results indicate that FLT3/ITD mutations may contribute to leukaemic transformation of normal HSPCs by prolonging survival, promoting proliferation and partially blocking differentiation. CEP‐701 may act as a potent therapeutic agent for AML stem cells harbouring FLT3/ITD mutations.