Trends in Immunology
Volume 32, Issue 9, September 2011, Pages 434-442
Journal home page for Trends in Immunology

Review
Notch in T-ALL: new players in a complex disease

https://doi.org/10.1016/j.it.2011.06.005Get rights and content

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic malignancy of thymocytes affecting preferentially children and adolescents. The disease is heterogeneous and characterized by a large set of chromosomal and genetic alterations that deregulate the growth of maturing thymocytes. The identification of activating point mutations in NOTCH1 in more then 50% of all T-ALL cases highlights the NOTCH1 cascade as a central player of T-ALL pathogenesis. In this review, we summarize and update more recent findings on the molecular mechanisms of T-ALL with a particular emphasis on the oncogenic properties of aberrant NOTCH1 signaling.

Section snippets

Notch signaling finds its place in T-ALL

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of developing thymocytes. The disease represents 15% of pediatric and 25% of adult acute lymphoblastic leukemia (ALL) cases. It is characterized clinically by high white blood cell counts, increased numbers of blast cells and enlarged mediastinal lymph nodes. Although the disease develops mostly in the thymus, it tends to spread throughout the body, including the central nervous system, complicating the therapeutic

Notch1 – key player in T-ALL

Notch signaling through the Notch1 receptor has long been shown to be essential for T cell lineage development, thymocyte survival, as well as the proliferation of committed T cell progenitors. Historically, the first evidence of Notch1 being involved in T-ALL was provided when NOTCH1 was identified through the analysis of a chromosomal translocation [t(7;9)(q34;q34.3)] detected in a small number of T-ALL patients. This revealed that a portion of the human NOTCH1 gene had translocated into the

Mechanistic differences in oncogenic Notch1 activation in mice and humans

Notch receptors comprise a large extracellular domain consisting of EGFR and a negative regulatory region (LNR) that prevents Notch proteolytic cleavage and activation in the absence of ligands (Figure 1). Thus, it is not surprising that during human T-ALL progression, there is a strong selection for ligand-independent NOTCH1 mutant alleles. The most common NOTCH1 mutations in human T-ALL are clustered within the hydrophobic core of the HD, allowing for ligand-independent cleavage. By contrast,

Affected signaling pathways by aberrant Notch signaling

It has long been known that Notch1 signaling is essential for normal T cell fate specification, as well as thymocyte maturation and progression through and beyond the β-selection checkpoint. Thus, it is not surprising that genes and signaling pathways identified downstream of Notch1 in T-ALL cell lines and in vivo mouse models are linked to their physiological role in normal T cell development. The function of aberrant Notch1 signaling in T-ALL can therefore be inferred from its normal purpose.

Tumor-promoting and suppressive miRNA in Notch-induced T-ALL

Micro RNAs (miRNAs), small noncoding RNAs of 19-22 nucleotides, play crucial roles in the translational regulation of protein expression by posttranscriptional silencing. miRNAs are fundamental regulators of physiologically significant cellular processes, and thus, it is not surprising that the deregulation of miRNAs seems to play an important role in human cancers. It has become obvious that miRNAs act as crucial regulators during tumorigenesis, either as oncogenes, as tumor suppressors or

Concluding remarks

Although T-ALL is a heterogeneous disease in which multiple genetic aberrations cooperate to deregulate proliferation, differentiation and survival of immature thymocytes, more than half of the patients carry activating mutations within the NOTCH1 gene, highlighting its central role in the disease. The oncogenic role of Notch1 is a reflection of its physiological function during normal T cell development. Notch1 is a master regulator for T cell lineage commitment and maturation. However, if

Acknowledgements

This work was supported in part by the Swiss National Science Foundation and Oncosuisse.

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