Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant

Stable Identifier
R-HSA-2660826
Type
Pathway
Species
Homo sapiens
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5/5
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Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant
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NOTCH1 t(7;9)(NOTCH1:M1580_K2555) mutant is expressed in a small subset of T-cell acute lymphoblastic leukemia (T-ALL) patients. This mutant protein results from a translocation that joins a portion of intron 24 of the NOTCH1 gene to the promoter sequence of T-cell receptor beta (TCRB), leading to overexpression of a truncated NOTCH1 protein in T-cells and their precursors. The truncated NOTCH1 contains amino acids 1580 to 2555 of the wild-type NOTCH1, lacking almost the entire extracellular domain, including EGF and LIN12 repeats (Ellisen et al. 1991). As EGF repeats are needed for NOTCH1 interaction with its ligands (DLL1, DLL4, JAG1, JAG2), the mutant NOTCH1 t(7;9)(NOTCH1:M1580_K2555) does not bind a ligand. The constitutive activity of NOTCH1 t(7;9)(NOTCH1:M1580_K2555) is based on its constitutive proteolytic processing into NOTCH1 intracellular domain (NICD1) by ADAM10/17 protease and gamma-secretase complex, as proteolytic cleavage sites are exposed in the absence of ligand binding in the mutant protein. Constitutively produced NICD1 accumulates in the nucleus, leading to aberrant activation of NOTCH1 target genes which play important roles in the development of T lymphocytes (Washburn et al. 1997. Radtke et al. 1999, Maillard et al. 2004, Sambandam et al. 2005, Tan et al. 2005). Infection of bone marrow cells with recombinant retroviruses that code for truncated NOTCH1 that resembles t(7;9)(NOTCH1:M1580_K2555) resulted in T-ALL-like illness in a portion of mice that received the infected bone-marrow transplant, with all tumors overexpressing truncated forms of NOTCH1 (Pear et al. 1996).
Literature References
PubMed ID Title Journal Year
10367900 Deficient T cell fate specification in mice with an induced inactivation of Notch1

Stark, G, Wilson, A, Bauer, M, MacDonald, HR, Aguet, M, van Meerwijk, J, Radtke, F

Immunity 1999
15187027 Mastermind critically regulates Notch-mediated lymphoid cell fate decisions

Carpenter, AC, Xu, L, Maillard, I, Pear, WS, Sai, H, Aster, JC, Allman, D, Weng, AP, Rodriguez, CG

Blood 2004
15951813 Notch signaling controls the generation and differentiation of early T lineage progenitors

Bhandoola, A, Gerstein, RM, Xu, L, Maillard, I, Pear, WS, Aster, JC, Sambandam, A, Zediak, VP

Nat. Immunol. 2005
15951812 Requirement for Notch1 signals at sequential early stages of intrathymic T cell development

Yuan, JS, Tan, JB, Guidos, CJ, Visan, I

Nat. Immunol. 2005
9118226 Notch activity influences the alphabeta versus gammadelta T cell lineage decision

Fowlkes, BJ, Chang, D, Washburn, T, Cado, D, Gridley, T, Schweighoffer, E, Robey, E

Cell 1997
1831692 TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms

Smith, SD, Sklar, J, Ellisen, LW, Bird, J, West, DC, Soreng, AL, Reynolds, TC

Cell 1991
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Disease
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
T-cell acute lymphoblastic leukemia DOID:5603
Authored
Orlic-Milacic, M  (2013-01-04)
Reviewed
Haw, R  (2013-02-10)
Created
Orlic-Milacic, M  (2012-11-24)
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