Evidence for Hox and E2A-PBX1 collaboration in mouse T-cell leukemia.
Using murine Moloney leukemia virus (MMLV)-based proviral insertional mutagenesis, we previously showed a preferential targeting of a small region in the Hoxa gene locus in E2A-PBX1-induced lymphoid leukemia resulting in the overexpression of several Hoxa genes including Hoxa10, Hoxa9 and Hoxa7. This observation suggested a functional interaction between Hox gene overexpression and E2A-PBX1 in lymphoid tumors. To further explore this possibility, we generated a series of compound E2A-PBX1 x Hox transgenic mice and tested the genetic interaction between these genes in the generation of lymphoid leukemia in vivo. Results presented in this report show that the onset of T-cell leukemia is significantly accelerated in E2A-PBX1 x Hoxb4 compound transgenic animals when compared with control E2A-PBX1 or Hoxb4 littermates. Hoxa9 appears less potent than Hoxb4 to accelerate E2A-PBX1-induced T-cell leukemia in mice. E2A-PBX1-induced T-cell leukemias express much higher levels of Hoxa genes than MMLV-induced counterparts, possibly suggesting a contribution of these genes to T-cell transformation by E2A-PBX1. Collectively, these data provide the first genetic evidence showing oncogenic collaboration between E2A-PBX1 and a Hox gene in lymphoid malignancies in vivo and document the specific deregulation of a subgroup of Hoxa genes in these leukemias.
Bijl
J
J
Laboratory of Molecular Genetics of Hematopoietic Stem Cells, Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Quebec, Canada. jbijl.hmr@ssss.gouv.qc.ca
Krosl
J
J
Lebert-Ghali
C-E
CE
Vacher
J
J
Mayotte
N
N
Sauvageau
G
G
D000818:Animals; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D015458:Leukemia, T-Cell / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008979:Moloney murine leukemia virus / Q000235:genetics; D016254:Mutagenesis, Insertional / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
D018398:Homeodomain Proteins; C513262:Hoxb4 protein, mouse; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; C097899:homeobox protein HOXA9; C089847:E2A-Pbx1 fusion protein