Recent Advances on NOTCH Signaling in T-ALL

Abstract

NOTCH1 receptor signaling plays a central role in T-cell lineage specification and in supporting the growth and proliferation of immature T-cell progenitors in the thymus during lymphoid development. In T-cell acute lymphoblastic leukemia (T-ALL), a tumor resulting from the malignant transformation of T-cell progenitors, aberrant and constitutively active NOTCH1 signaling triggered by activating mutations in the NOTCH1 gene contributes to oncogenic transformation and is a hallmark of this disease. Most notably, small molecule γ-secretase inhibitors (GSIs) can effectively block NOTCH1 signaling in T-ALL, and could be exploited as a targeted therapy in this disease. In addition, a number of emerging anti-NOTCH therapeutic strategies including anti-NOTCH1 inhibitory antibodies, small peptide inhibitors of NOTCH signaling and combination therapies with GSIs and glucocorticoids, have recently been proposed. Finally, the identification of NOTCH1 mutations in solid tumors and chronic lymphocytic leukemias has increased even further the clinical relevance of NOTCH signaling as a therapeutic target in human cancer. Here we review our current understanding of NOTCH1-induced transformation, the mechanisms of action of oncogenic NOTCH1 in T-ALL and the therapeutic and prognostic implications of NOTCH1 mutations in T-ALL.

Long-range enhancer activity determines Myc sensitivity to Notch inhibitors in T cell leukemia

“…MAML also recruits proteins leading to NICD degradation (3). The activating Notch1 mutations in T-ALL lead to either ligand-independent ADAM metalloprotease cleavage and/or diminished NICD degradation (4).…”

How I treat T-cell acute lymphoblastic leukemia in adults

“…NOTCH1 was first discovered as a partner gene in the t(7;9)(q34;q34) chromosomal translocation 16 and was later implicated in the pathogenesis of up to 60% of T-ALL, harboring activating mutations, involving negative regulatory domains responsible for the control of initiation and termination of NOTCH signaling. 17,18 Additionally, it was found that mutations in the FBXW7 gene are present in 15% of T-ALL cases, and these interfere with the proteasomal degradation of activated NOTCH1 protein. [18][19][20][21] In addition to NOTCH1 mutations, T-ALLs frequently show T-cell receptor gene chromosomal translocations, resulting in aberrant expression of transcription factor oncogenes, such as TAL1, LMO1, LMO2, TLX1, and TLX3.…”

“…17,18 Additionally, it was found that mutations in the FBXW7 gene are present in 15% of T-ALL cases, and these interfere with the proteasomal degradation of activated NOTCH1 protein. [18][19][20][21] In addition to NOTCH1 mutations, T-ALLs frequently show T-cell receptor gene chromosomal translocations, resulting in aberrant expression of transcription factor oncogenes, such as TAL1, LMO1, LMO2, TLX1, and TLX3. 15 Furthermore, mutations in the IL7R, JAK1, and JAK3 genes activate the IL7R/ JAK-STAT pathway, and loss of the PTEN tumor suppressor gene drives aberrant phosphatidylinositol 3-kinase (PI3K)-AKT signaling.…”

Role of different aberrant cell signalling pathways prevalent in acute lymphoblastic leukemia

“…With all the studies linking aberrant Notch1 signalling effectively to the pathogenesis of T-ALL, it makes a promising therapeutic target towards T-ALL treatment (Radtke et al 2005;Palomero & Ferrando 2009). Small molecule inhibitors of γ-secretase (GSIs) capable of blocking Notch1 activation have prompted clinical trials to test their effectiveness against T-ALL ( Tzoneva & Ferrando 2012). Initial studies on human T-ALL cell lines harbouring activating mutations in Notch1 treated with GSIs confirms that inhibition of Notch signalling arrests cells at G0/G1 phase (Palomero et al 2006;Lewis et al 2007;Rao et al 2009).…”