Continuous MLL-ENL expression is necessary to establish a "Hox Code" and maintain immortalization of hematopoietic progenitor cells.
The t[(11;19)(p22;q23)] translocation, which gives rise to the MLL-ENL fusion protein, is commonly found in infant acute leukemias of both the myeloid and lymphoid lineage. To investigate the molecular mechanism of immortalization by MLL-ENL we established a Tet-regulatable system of MLL-ENL expression in primary hematopoietic progenitor cells. Immortalized myeloid cell lines were generated, which are dependent on continued MLL-ENL expression for their survival and proliferation. These cells either terminally differentiate or die when MLL-ENL expression is turned off with doxycycline. The expression profile of all 39 murine Hox genes was analyzed in these cells by real-time quantitative PCR. This analysis showed that loss of MLL-ENL was accompanied by a reduction in the expression of multiple Hoxa genes. By comparing these changes with Hox gene expression in cells induced to differentiate with granulocyte colony-stimulating factor, we show for the first time that reduced Hox gene expression is specific to loss of MLL-ENL and is not a consequence of differentiation. Our data also suggest that the Hox cofactor Meis-2 can substitute for Meis-1 function. Thus, MLL-ENL is required to initiate and maintain immortalization of myeloid progenitors and may contribute to leukemogenesis by aberrantly sustaining the expression of a "Hox code" consisting of Hoxa4 to Hoxa11.
Horton
Sarah J
SJ
Molecular Haematology and Cancer Biology Unit, Institute of Child Health, University College London.
Grier
David G
DG
McGonigle
Glenda J
GJ
Thompson
Alexander
A
Morrow
Michelle
M
De Silva
Inusha
I
Moulding
Dale A
DA
Kioussis
Dimitris
D
Lappin
Terence R J
TR
Brady
Hugh J M
HJ
Williams
Owen
O
D000818:Animals; D002461:Cell Line, Transformed; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000502:physiology*; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D051788:Myeloid-Lymphoid Leukemia Protein / Q000096:biosynthesis* / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis* / Q000235:genetics; D012190:Retroviridae / Q000235:genetics; D014157:Transcription Factors
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C484111:Hoxa4 protein, mouse; C425207:MLL-ENL oncoprotein, human; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; C088144:HoxA protein