Enforced expression of HOX11 is associated with an immature phenotype in J2E erythroid cells.
The HOX11 gene encodes a homeodomain transcription factor that is essential for spleen development during embryogenesis. HOX11 is also leukaemogenic, both through its clinical association with childhood T-cell acute lymphoblastic leukaemia, and its ability to immortalize other haematopoietic cell lineages experimentally. To examine the pathological role of HOX11 in tumorigenesis, we constitutively expressed HOX11 cDNA in J2E murine erythroleukaemic cells, which are capable of terminal differentiation. Enforced HOX11 expression was found to induce a profound alteration in J2E cellular morphology and differentiation status. Our analyses revealed that HOX11 produced clones with a preponderance of less differentiated cells that were highly adherent to plastic. Morphologically, the cells overexpressing HOX11 were larger and had decreased globin levels, as well as a reduction in haemoglobin synthesis in response to erythropoietin (EPO). Immunocytochemical analysis confirmed the immature erythroid phenotype imposed by HOX11, with clones transfected with HOX11 demonstrating expression of the c-Kit stem cell marker, while retaining EPO receptor expression. Taken together, these results show that HOX11 alters erythroid differentiation, favouring a less mature progenitor-like stage. This supports the notion that disrupted haematopoietic cell differentiation is responsible for pre-leukaemic immortalization by the HOX11 oncoprotein.
Greene
Wayne K
WK
Division of Children's Leukaemia and Cancer Research, TVW Telethon Institute for Child Health Research and Centre for Child Health Research, University of Western Australia, West Perth, Australia. W.Greene@murdoch.edu.au
Ford
Jette
J
Dixon
Darcelle
D
Tilbrook
Peta A
PA
Watt
Paul M
PM
Klinken
S Peter
SP
Kees
Ursula R
UR
D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D048429:Cell Size / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D018076:DNA, Complementary / Q000235:genetics; D015672:Erythroid Precursor Cells / Q000378:metabolism*; D005801:Genes, Homeobox; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D004915:Leukemia, Erythroblastic, Acute / Q000378:metabolism*; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014407:Tumor Cells, Cultured
D018076:DNA, Complementary; D018398:Homeodomain Proteins; D009363:Neoplasm Proteins; D015513:Oncogene Proteins; C487378:Tlx1 protein, mouse