p16INK4A tumor suppressor gene expression and CD3epsilon deficiency but not pre-TCR deficiency inhibit TAL1-linked T-lineage leukemogenesis.
Inactivation of the CDKN2 genes that encode the p16(INK4A) and p14(ARF) proteins occurs in the majority of human T-cell acute lymphoblastic leukemias (T-ALLs). Ectopic expression of TAL1 and LMO1 genes is linked to the development of T-ALL in humans. In TAL1xLMO1 mice, leukemia develops in 100% of mice at 5 months. To identify the molecular events crucial to leukemic transformation, we produced several mouse models. We report here that expression of P16(INK4A) in developing TAL1xLMO1 thymocytes blocks leukemogenesis in the majority of the mice, and the leukemias that eventually develop show P16(INK4A) loss of expression. Events related to the T-cell receptor beta selection process are thought to be important for leukemic transformation. We show here that the absence of the pTalpha chain only slightly delays the appearance of TAL1xLMO1-induced T-ALL, which indicates a minor role of the pTalpha chain. We also show that the CD3epsilon-mediated signal transduction pathway is essential for this transformation process, since the TAL1xLMO1xCD3epsilon-deficient mice do not develop T-ALL for up to 1 year.
Fasseu
Magali
M
Institut National de la Santé et de la Recherche Médicale (INSERM) U462, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France.
Aplan
Peter D
PD
Chopin
Martine
M
Boissel
Nicolas
N
Bories
Jean-Christophe
JC
Soulier
Jean
J
von Boehmer
Harald
H
Sigaux
François
F
Regnault
Armelle
A
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D017252:CD3 Complex / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D019070:Cell Lineage; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D056743:Cyclin D3; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D016213:Cyclins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D060588:LIM Domain Proteins; D007938:Leukemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D017252:CD3 Complex; D056743:Cyclin D3; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016213:Cyclins; D060588:LIM Domain Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D051881:Receptor, Notch1; D011948:Receptors, Antigen, T-Cell; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors; C534696:CCND3 protein, human; C115335:CD3E protein, human; C534697:Ccnd3 protein, mouse; C513044:Lmo1 protein, mouse; C489366:Tal1 protein, mouse; C067143:TAL1 protein, human