The mechanism of hematopoietic progenitor cell immortalization by MLL-ENL.
The t(11;19) translocation gives rise to the MLL-ENL fusion protein and is frequently found in infant myeloid and lymphoid leukemias. Immortalized myeloid cell lines can be generated by expression of MLL-ENL in murine hematopoietic progenitors. By establishing myeloid cell lines with conditional expression of MLL-ENL, we recently demonstrated that MLL-ENL is necessary to maintain immortalization and sustain the expression of a characteristic pattern of Hox genes. The cell lines can be induced to undergo terminal differentiation by inhibition of MLL-ENL expression or by treatment with G-CSF. Expression of Hoxa genes is reduced in cells differentiating as a result of MLL-ENL loss, but is maintained in G-CSF treated cells. Thus, although aberrant maintenance of Hoxa gene expression may play an important role in MLL-ENL induced leukemia, the contribution of this pathway to immortalization is critically dependent on the cytokine environment of the immortalized myeloid cells.
Molecular Haematology and Cancer Biology Unit, Institute of Child Health, University College London, United Kingdom.
Sarah J
SJ
Horton
Owen
O
Williams
D000818:Animals; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*
C425207:MLL-ENL oncoprotein, human; D015514:Oncogene Proteins, Fusion; D016179:Granulocyte Colony-Stimulating Factor; D051788:Myeloid-Lymphoid Leukemia Protein