Oncogenesis of T-ALL and nonmalignant consequences of overexpressing intracellular NOTCH1
- PMID: 18981238
- PMCID: PMC2585834
- DOI: 10.1084/jem.20081561
Oncogenesis of T-ALL and nonmalignant consequences of overexpressing intracellular NOTCH1
Abstract
Mutations resulting in overexpression of intracellular Notch1 (ICN1) are frequently observed in human T cell acute lymphoblastic leukemia (T-ALL). We have determined the consequences of ICN1 overexpression from retroviral vectors introduced into bone marrow cells. Early consequences are the generation of polyclonal nontumorigenic CD4(+)8(+) T cell receptor (TCR)-alphabeta(+) cells that do not qualify as tumor precursors despite the observation that they overexpress Notch 1 and c-Myc and degrade the tumor suppressor E2A by posttranslational modification. The first tumorigenic cells are detected among more immature CD4(-)8(+)TCR-alphabeta(-) cells that give rise to monoclonal tumors with a single, unique TCR-beta chain and diverse TCR-alpha chains, pinpointing malignant transformation to a stage after pre-TCR signaling and before completion of TCR-alpha rearrangement. In T-ALL, E2A deficiency is accompanied by further transcriptional up-regulation of c-Myc and concomitant dysregulation of the c-Myc-p53 axis at the transcriptional level. Even though the tumors consist of phenotypically heterogeneous cells, no evidence for tumor stem cells was found. As judged by array-based comparative genomic hybridization (array CGH) and spectral karyotype (SKY) analysis, none of the tumors arise because of genomic instability.
Figures
![Figure 1.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2585834/bin/jem2052851f01.gif)
![Figure 2.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2585834/bin/jem2052851f02.gif)
![Figure 3.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2585834/bin/jem2052851f03.gif)
![Figure 4.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2585834/bin/jem2052851f04.gif)
![Figure 5.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2585834/bin/jem2052851f05.gif)
![Figure 6.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2585834/bin/jem2052851f06.gif)
![Figure 7.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2585834/bin/jem2052851f07.gif)
![Figure 8.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2585834/bin/jem2052851f08.gif)
Similar articles
-
Haploinsufficiency of the c-myc transcriptional repressor FIR, as a dominant negative-alternative splicing model, promoted p53-dependent T-cell acute lymphoblastic leukemia progression by activating Notch1.Oncotarget. 2015 Mar 10;6(7):5102-17. doi: 10.18632/oncotarget.3244. Oncotarget. 2015. PMID: 25671302 Free PMC article.
-
The Notch driven long non-coding RNA repertoire in T-cell acute lymphoblastic leukemia.Haematologica. 2014 Dec;99(12):1808-16. doi: 10.3324/haematol.2014.115683. Epub 2014 Oct 24. Haematologica. 2014. PMID: 25344525 Free PMC article.
-
Notch1 contributes to mouse T-cell leukemia by directly inducing the expression of c-myc.Mol Cell Biol. 2006 Nov;26(21):8022-31. doi: 10.1128/MCB.01091-06. Epub 2006 Sep 5. Mol Cell Biol. 2006. PMID: 16954387 Free PMC article.
-
The NOTCH1-MYC highway toward T-cell acute lymphoblastic leukemia.Blood. 2017 Mar 2;129(9):1124-1133. doi: 10.1182/blood-2016-09-692582. Epub 2017 Jan 23. Blood. 2017. PMID: 28115368 Review.
-
Notch1 and IL-7 receptor signalling in early T-cell development and leukaemia.Curr Top Microbiol Immunol. 2012;360:47-73. doi: 10.1007/82_2012_231. Curr Top Microbiol Immunol. 2012. PMID: 22695916 Review.
Cited by
-
Notch signaling pathway in cancer: from mechanistic insights to targeted therapies.Signal Transduct Target Ther. 2024 May 27;9(1):128. doi: 10.1038/s41392-024-01828-x. Signal Transduct Target Ther. 2024. PMID: 38797752 Free PMC article. Review.
-
RNA helicase DHX15 exemplifies a unique dependency in acute leukemia.Haematologica. 2023 Aug 1;108(8):2029-2043. doi: 10.3324/haematol.2022.282066. Haematologica. 2023. PMID: 36861414 Free PMC article.
-
A double-negative thymocyte-specific enhancer augments Notch1 signaling to direct early T cell progenitor expansion, lineage restriction and β-selection.Nat Immunol. 2022 Nov;23(11):1628-1643. doi: 10.1038/s41590-022-01322-y. Epub 2022 Oct 31. Nat Immunol. 2022. PMID: 36316479 Free PMC article.
-
The Role of NOTCH1, GATA3, and c-MYC in T Cell Non-Hodgkin Lymphomas.Cancers (Basel). 2022 Jun 4;14(11):2799. doi: 10.3390/cancers14112799. Cancers (Basel). 2022. PMID: 35681778 Free PMC article. Review.
-
Inhibition of mitochondrial complex I reverses NOTCH1-driven metabolic reprogramming in T-cell acute lymphoblastic leukemia.Nat Commun. 2022 May 19;13(1):2801. doi: 10.1038/s41467-022-30396-3. Nat Commun. 2022. PMID: 35589701 Free PMC article.
References
-
- Artavanis-Tsakonas, S., M.D. Rand, and R.J. Lake. 1999. Notch Signaling: Cell fate control and signal integration in development. Science. 284:770–776. - PubMed
-
- Weng, A.P., A.A. Ferrando, W. Lee, J.P.T. Morris, L.B. Silverman, C. Sanchez-Irizarry, S.C. Blacklow, A.T. Look, and J.C. Aster. 2004. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 306:269–271. - PubMed
-
- Palomero, T., W.K. Lim, D.T. Odom, M.L. Sulis, P.J. Real, A. Margolin, K.C. Barnes, J. O'Neil, D. Neuberg, A.P. Weng, et al. 2006. NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth. Proc. Natl. Acad. Sci. USA. 103:18261–18266. - PMC - PubMed
Publication types
MeSH terms
Substances
Associated data
- Actions
Grants and funding
LinkOut - more resources
Full Text Sources
Medical
Research Materials
Miscellaneous