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| Subject Categories: Cell Cycle | Genome Stability & Dynamics |
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| The EMBO Journal
(2002) 21, 4297–4306, doi: 10.1093/emboj/cdf429 |
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| MLL−ENL cooperates with SCF to transform primary avian multipotent cells |
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| Cathleen E. Schulte1, 2, 3, Marieke von Lindern4, Peter Steinlein2, Hartmut Beug2, 6 and Leanne M. Wiedemann1, 5, 6 |
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1 Leukaemia Research Fund Centre at the Institute of Cancer Research, London, UK 2 Institute of Molecular Pathology, Vienna, Austria 3 Institute of Molecular Pathology, Dr Bohr Gasse 7, 1030 Vienna, Austria 4 Institute of Hematology, Erasmus University, Rotterdam, The Netherlands 5 Stowers Institute for Medical Research, 1000 E 50th Street, Kansas City, MO 64110, USA 6 H.Beug and L.M.Wiedemann contributed equally to this work To whom correspondence should be addressed Cathleen E. Schulte, schulte@nt.imp.univie.ac.at Received 16 January 2002; Revised 16 May 2002; Accepted 1 July 2002. |
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| Abstract |
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| The MLL gene is targeted by chromosomal translocations, which give rise to heterologous MLL fusion proteins and are associated with distinct types of acute lymphoid and myeloid leukaemia. To determine how MLL fusion proteins alter the proliferation and/or differentiation of primary haematopoietic progenitors, we introduced the MLL−AF9 and MLL−ENL fusion proteins into primary chicken bone marrow cells. Both fusion proteins caused the sustained outgrowth of immature haematopoietic cells, which was strictly dependent on stem cell factor (SCF). The renewing cells have a long in vitro lifespan exceeding the Hayflick limit of avian cells. Analysis of clonal cultures identified the renewing cells as immature, multipotent progenitors, expressing erythroid, myeloid, lymphoid and stem cell surface markers. Employing a two-step commitment/differentiation protocol involving the controlled withdrawal of SCF, the MLL−ENL-transformed progenitors could be induced to terminal erythroid or myeloid differentiation. Finally, in cooperation with the weakly leukaemogenic receptor tyrosine kinase v-Sea, the MLL−ENL fusion protein gave rise to multilineage leukaemia in chicks, suggesting that other activated, receptor tyrosine kinases can substitute for ligand-activated c-Kit in vivo. |
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| Keywords: c-Kit, leukaemia, MLL, multipotent progenitor, receptor tyrosine kinases |
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