Notch/HES1-mediated PARP1 activation: a cell type–specific mechanism for tumor suppression

Abstract

IntroductionAcute lymphoblastic leukemia (ALL) is the most common malignancy diagnosed in children and is a prevalent form of adult acute leukemia. 1,2 Although outcomes among children with ALL have improved dramatically, children who relapse and adults with ALL have a poor prognosis, with Ͻ 40% long-term survival. 1,3 Despite dose intensification and widespread use of stem cell transplantation in relapse, little improvement in salvage rates has occurred. Hence, novel therapies, particularly those that target critical growth and survival pathways, are needed.Numerous studies have shown that dysregulated cell signaling is extensively involved in tumor initiation, promotion, and progression. Indeed, dysregulation of the Notch pathway has been shown in a wide range of tumors, including T-cell leukemia/lymphoma, breast carcinomas, pancreatic carcinomas, and so forth. 4 In T-cell ALL, Notch pathways are constitutively activated in more than one-half of all cases through activating mutations in the Notch1 receptor. 5,6 In contrast, Notch1 mutations have not been found in B-cell ALL, and evidence supports an inhibitory role for Notch signaling in normal and malignant B cells. [7][8][9] These studies show contrasting cell type-specific consequences of Notch signaling and mirror the developmental role of Notch signaling in commitment and expansion of T cells at the expense of B cells. [10][11][12] Therefore, Notch signaling provides a highly conserved pathway that regulates lymphocyte cell lineage and plays contrasting roles in T-and B-cell leukemias. 13,14 In mammals, there are 4 Notch receptors (Notch1-4) and 5 Notch ligands (Jagged1/2, Delta-like 1/2/4). 15 Once bound to ligand, the Notch receptors are cleaved by ␥-secretase, which leads to liberation and translocation of the Notch intracellular domain to the nucleus. 16 Within the nucleus, all 4 Notch intracellular domains bind to and displace co-repressors from the transcription factor CSL (derived from CBF-1, Su(H), and Lag2, also known as RBP-J) to generate a transactivation complex, thereby initiating transcription of CSL target genes such as members of the hairy/ enhancer of split (HES) family. 17,18 Because all 4 Notch receptors signal through the same CSLdependent pathways, we hypothesized that downstream targets of Notch/CSL may be responsible for the contrasting roles of Notch signaling. Indeed, we found that HES1 expression is sufficient to reproduce the Notch effects in B-cell ALL (B-ALL) but does not affect growth or survival in T-cell ALL (T-ALL). 9 In support of this, HES1 has been shown to mimic Notch inhibition of normal B-cell development. 19 HES1 is the most commonly described Notch/CSL target gene 17 and appears to contribute to T-cell leukemogenesis. 20 It encodes a basic helix-loop-helix (bHLH) transcription factor, which is known to recruit co-repressors of the transducin-like enhancer (TLE, groucho) of split family. 21 Through its bHLH domain, HES1, forms homodimers and heterodimers that bind to a variety of modified E-box binding sites with...

Loss of p19Arf in a Rag1−/− B-cell precursor population initiates acute B-lymphoblastic leukemia

“…This can be indicative of Notch1 providing different effects at the time point of initiation and maintenance of leukemia. Further experiments will be necessary to declare the role of Notch1 at different stages of leukemia development 26 The corresponding Sca1 low ckit low CD19 ϩ Rag1-deficient Bprecursor population expressed p19Arf. Signer et al have described the expression of p19Arf in B-precursor cells at the CLP to pre-B-cell stage in young WT mice.…”

HES1 in immunity and cancer

“…HES1 also induces activation of PARP1 in B-cell acute lymphoblastic leukaemia (ALL) to induce apoptosis and tumor suppressive activity [13]. Thus, HES1 may function as either repressors or activators depending on the transcriptional complexes and thereby establishing a potential mechanism of cell specific dependent regulation.…”

Tigecycline Inhibits Glioma Growth by Regulating miRNA-199b-5p–HES1–AKT Pathway

“…Overexpression of HES1 is associated with a variety of human cancers, including T-cell acute lymphoblastic leukemia (ALL) and breast, cervical, prostate, ovarian, colon, and non-small cell lung cancer (NSCLC; refs. [21][22][23][24][25]. Recently, HES1 was shown as a self-renewal marker in cancer cells, and it enhanced the tumor-initiating capacity of tumor cells in nude mice (25).…”