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Primary literature review
Activating Mutations of NOTCH1 in Human T Cell Acute Lymphoblastic Leukemia
Weng, A.P. et al. [1]
Activating Mutations of NOTCH1 in Human T Cell Acute Lymphoblastic Leukemia
Weng, A.P. et al. [1]
T-cell acute lymphoblastic leukemia (T-ALL) is a form of cancer characterized by overproliferation of immature T-cells. Efforts to identify the genetic factors behind this cancer have identified NOTCH1, a transmembrane receptor, as a possible contributor to T-ALL. NOTCH1 was first discovered in a translocation involving chromosome 7 and 9 [2]. However, such mutation accounts for less than 1% of T-ALL cases [3]. In this paper, the authors studied the role of NOTCH1 in human T-ALL, intending to identify other forms of mutations in this gene that may be implicated in T-ALL. They isolated and sequenced NOTCH1 from human T-ALL cell lines that are dependent on Notch1 signaling. From the gene sequencing results, they found that 4/5 of these cell lines have missense mutations and/or frameshift mutations (see insertions and deletions) in NOTCH1. Apart from that, the authors also analyzed bone marrow samples of children and adolescent T-ALL patients, and discovered that over half of the samples carry missense and/or frameshift mutations in the NOTCH1 gene. Together, these information suggest that NOTCH1 may be an important contributor to the development of T-ALL.
The pathology of NOTCH1 mutation(s) could be appreciated via an understanding of how normal Notch1 protein functions in biological systems. In its normal state, Notch1 protein functions as a receptor that plays a role in the regulation of T-cell proliferation, transformation, and death [4]. Hence, mutations in NOTCH1 gene could lead to aberrant signaling and give rise to T-ALL. In this article, analysis of bone marrow samples from human T-ALL patients revealed that NOTCH1 mutations cluster in certain “hotspots” rather than being randomly spread. These mutations are thought to increase the production or enhance the stability of the signaling molecule, leading to abnormal proliferation of T-cell blasts. Another important piece of information reported in this paper is that no mutations in NOTCH1 were observed in the bone marrow samples of patients whose T-ALL have remitted. This means that NOTCH1 mutation is specific to leukemic cells. Hence, the authors concluded that NOTCH1 mutation plays a significant role in T-ALL, and drugs that target the Notch signaling pathway may be effective against T-ALL.
The pathology of NOTCH1 mutation(s) could be appreciated via an understanding of how normal Notch1 protein functions in biological systems. In its normal state, Notch1 protein functions as a receptor that plays a role in the regulation of T-cell proliferation, transformation, and death [4]. Hence, mutations in NOTCH1 gene could lead to aberrant signaling and give rise to T-ALL. In this article, analysis of bone marrow samples from human T-ALL patients revealed that NOTCH1 mutations cluster in certain “hotspots” rather than being randomly spread. These mutations are thought to increase the production or enhance the stability of the signaling molecule, leading to abnormal proliferation of T-cell blasts. Another important piece of information reported in this paper is that no mutations in NOTCH1 were observed in the bone marrow samples of patients whose T-ALL have remitted. This means that NOTCH1 mutation is specific to leukemic cells. Hence, the authors concluded that NOTCH1 mutation plays a significant role in T-ALL, and drugs that target the Notch signaling pathway may be effective against T-ALL.
References:
1. Weng, A.P., Ferrando, A.A., Lee, W., Morris IV, J.P., Silverman, L.B., Sanchez-Irizarry, C., Blacklow, S.C., Look, A.T., & Aster, J.C. (2004). Activating Mutations of NOTCH1 in Human T cell Acute Lymphoblastic Leukemia. Science 306 (5694) :269-271. doi: 10.1126/science.1102160.
2. Aster, J.C et al. (2011). Notch signalling in T-cell lymphoblastic leukemia/lymphoma and other haematological malignancies. J Pathol 223: 262-273. doi: 10.1002/path.2789.
3. Ellisen, L.W., Bird, J., West, D.C., Soreng, A.L., Reynolds, T.C., Smith, S.D., & Sklar, J. (1991). TAN-1, the human homolog of the Drosophila Notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 66(4): 649-661. doi: 10.1016/0092-8674(91)90111-B.
4. Demarest, R.M., Ratti, F., & Capobianco, A.J. (2008) It’s all about Notch. Oncogene 27: 5082-5091. doi:10.1038/onc.2008.222.