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.
Horton
Sarah J
SJ
Molecular Haematology and Cancer Biology Unit, Institute of Child Health, University College London, United Kingdom.
Williams
Owen
O
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