The molecular basis of T cell acute lymphoblastic leukemia
Pieter Van Vlierberghe, Adolfo Ferrando
Pieter Van Vlierberghe, Adolfo Ferrando
Published October 1, 2012
Citation Information: J Clin Invest. 2012;122(10):3398-3406. https://doi.org/10.1172/JCI61269.
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Review Series

The molecular basis of T cell acute lymphoblastic leukemia

Abstract

T cell acute lymphoblastic leukemias (T-ALLs) arise from the malignant transformation of hematopoietic progenitors primed toward T cell development, as result of a multistep oncogenic process involving constitutive activation of NOTCH signaling and genetic alterations in transcription factors, signaling oncogenes, and tumor suppressors. Notably, these genetic alterations define distinct molecular groups of T-ALL with specific gene expression signatures and clinicobiological features. This review summarizes recent advances in our understanding of the molecular genetics of T-ALL.

Authors

Pieter Van Vlierberghe, Adolfo Ferrando

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Figure 1

Schematic representation of NOTCH1 signaling in T cell progenitors.

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Schematic representation of NOTCH1 signaling in T cell progenitors. Inte...
Interaction of the NOTCH ligand delta-like 4, expressed on the surface of thymic stroma cells, with NOTCH1 triggers a double proteolytic cleavage of the receptor in T cell progenitors first by the ADAM10 metalloprotease and subsequently by the gamma secretase complex. Release of the intracellular domains of NOTCH1 from the membrane activates the expression of NOTCH target genes in the nucleus. FBXW7 recognizes the PEST domain of activated NOTCH1 and terminates NOTCH signaling in the proteasome. Inhibition of ADAM10 cleavage with anti-NOTCH1 inhibitory antibodies, blockage of γ-secretase activity with small-molecule inhibitors, and disruption of the NOTCH1 nuclear transcriptional complex with small SAMH1 peptides are all approaches to effectively block NOTCH1 signaling in T-ALL.