FLT3/ITD expression increases expansion, survival and entry into cell cycle of human haematopoietic stem/progenitor cells

Li Li, Obdulio Piloto, Kyu Tae Kim, Zhaohui Ye, Bao Nguyen Ho, Xiaobing Yu, Mark Levis, Linzhao Cheng, Donald Small

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)64-75
Number of pages12
JournalBritish journal of haematology
Volume137
Issue number1
DOIs
StatePublished - Apr 2007

Keywords

  • Acute myeloid leukaemia
  • FLT3
  • Haematopoietic stem/progenitor cells
  • Internal tandem duplication
  • Leukaemic transformation

ASJC Scopus subject areas

  • Hematology

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