Abstract
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.
Publication types
-
Research Support, N.I.H., Intramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Basic Helix-Loop-Helix Transcription Factors / genetics
-
Basic Helix-Loop-Helix Transcription Factors / metabolism*
-
CD3 Complex / genetics
-
CD3 Complex / metabolism*
-
Cell Differentiation
-
Cell Lineage
-
Cell Transformation, Neoplastic / genetics
-
Cell Transformation, Neoplastic / metabolism*
-
Cell Transformation, Neoplastic / pathology
-
Cyclin D3
-
Cyclin-Dependent Kinase Inhibitor p16 / genetics
-
Cyclin-Dependent Kinase Inhibitor p16 / metabolism*
-
Cyclins / metabolism
-
Gene Expression Regulation, Neoplastic
-
Humans
-
LIM Domain Proteins
-
Leukemia / genetics
-
Leukemia / metabolism*
-
Leukemia / pathology*
-
Mice
-
Mice, Transgenic
-
Mutation / genetics
-
Nuclear Proteins / genetics
-
Nuclear Proteins / metabolism
-
Proto-Oncogene Proteins / genetics
-
Proto-Oncogene Proteins / metabolism*
-
RNA, Messenger / genetics
-
Receptor, Notch1 / genetics
-
Receptor, Notch1 / metabolism
-
Receptors, Antigen, T-Cell / deficiency
-
Receptors, Antigen, T-Cell / genetics
-
Receptors, Antigen, T-Cell / metabolism
-
Survival Rate
-
T-Cell Acute Lymphocytic Leukemia Protein 1
-
Thymus Gland / cytology
-
Thymus Gland / metabolism
-
Transcription Factors / genetics
-
Transcription Factors / metabolism
Substances
-
Basic Helix-Loop-Helix Transcription Factors
-
CCND3 protein, human
-
CD3 Complex
-
CD3E protein, human
-
Ccnd3 protein, mouse
-
Cyclin D3
-
Cyclin-Dependent Kinase Inhibitor p16
-
Cyclins
-
LIM Domain Proteins
-
Lmo1 protein, mouse
-
Nuclear Proteins
-
Proto-Oncogene Proteins
-
RNA, Messenger
-
Receptor, Notch1
-
Receptors, Antigen, T-Cell
-
T-Cell Acute Lymphocytic Leukemia Protein 1
-
Tal1 protein, mouse
-
Transcription Factors
-
TAL1 protein, human