SCL and LMO1 alter thymocyte differentiation: inhibition of E2A-HEB function and pre-T alpha chain expression.
Cooperation between the stem cell leukemia (SCL) transcription factor and its nuclear partners LMO1 or LMO2 induces aggressive T cell acute lymphoblastic leukemia when inappropriately expressed in T cells. This study examined the cellular and molecular targets of the SCL-LMO complex at the preleukemic stage. We show that SCL and its partners are coexpressed in the most primitive thymocytes. Maturation to the pre-T cell stage is associated with a down-regulation of SCL and LMO1 and LMO2, and a concomitant up-regulation of E2A and HEB expression. Moreover, enforced expression of SCL-LMO1 inhibits T cell differentiation and recapitulates a loss of HEB function, causing a deregulation of the transition checkpoint from the CD4-CD8- to CD4+CD8+ stages. Finally, we identify the gene encoding pT alpha as a downstream target of HEB that is specifically repressed by the SCL-LMO complex.
Herblot
S
S
Clinical Research Institute of Montréal, Montréal, Québec, Canada H2W1R7.
Steff
A M
AM
Hugo
P
P
Aplan
P D
PD
Hoang
T
T
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D015704:CD4 Antigens / Q000235:genetics; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D060588:LIM Domain Proteins; D008562:Membrane Glycoproteins / Q000235:genetics*; D008667:Metalloproteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D051792:Basic Helix-Loop-Helix Proteins; D015704:CD4 Antigens; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; D008562:Membrane Glycoproteins; D008667:Metalloproteins; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors; C065072:LMO1 protein, human; C085117:LMO2 protein, human; C513044:Lmo1 protein, mouse; C513188:Lmo2 protein, mouse; C407909:TCF3 protein, human; C489366:Tal1 protein, mouse; C489532:Tcf12 protein, mouse; C090377:pre-T cell receptor alpha; C067143:TAL1 protein, human; C073366:TCF12 protein, human