Notch signaling: switching an oncogene to a tumor suppressor

Abstract

The Notch signaling pathway is a regulator of self-renewal and differentiation in several tissues and cell types. Notch is a binary cell-fate determinant, and its hyperactivation has been implicated as oncogenic in several cancers including breast cancer and T-cell acute lymphoblastic leukemia (T-ALL). Recently, several studies also unraveled tumor-suppressor roles for Notch signaling in different tissues, including tissues where it was before recognized as an oncogene in specific lineages. Whereas involvement of Notch as an oncogene in several lymphoid malignancies (T-ALL, B-chronic lymphocytic leukemia, splenic marginal zone lymphoma) is well characterized, there is growing evidence involving Notch signaling as a tumor suppressor in myeloid malignancies. It therefore appears that Notch signaling pathway's oncogenic or tumor-suppressor abilities are highly context dependent. In this review, we summarize and discuss latest advances in the understanding of this dual role in hematopoiesis and the possible consequences for the treatment of hematologic malignancies.

Figure 1

Mammal Notch receptors, ligands, and canonical activation pathway. (A) Notch ligands and receptors. There are 5 Notch ligands in mammals: Jagged1, Jagged2, Delta-like1 (Dll1), Delta-like3 (Dll3), and Delta-like4 (Dll4). All ligands have an extracellular domain called DSL (Delta, Serrate, and Lag-2) involved in receptor binding associated with EGF-like repeats. There are 4 Notch receptors in mammals: Notch1 to Notch4. The extracellular domain of the 4 receptors has 3 negative regulatory LIN repeats but varies in the number of EGF-like repeats. The cytoplasmic portion of the receptor contains a RAM domain, nuclear localization signal (NLS), ankyrin (ANK) repeats, and a PEST domain regulating protein stability. Notch1 and Notch 2 have TADs; however, they are absent in Notch3 and Notch4. (B) Cognate interaction between Notch receptors and Notch ligands (Jagged/Delta) triggers 2 consecutive proteolytic cleavages by the ADAM10 metalloprotease and the γ-secretase complex. This generates ICN, the signaling portion of the receptor, which enters the nucleus and displaces corepressors (SMRT and CtBP1) and recruits the coactivator MAML1 and the acetyltransferase p300. ICN activating complex is short-lived, and ICN gets phosphorylated on its PEST domain and subsequently ubiquitinated by Fbw7 and targeted for degradation by the proteasome. ADP, adenosine diphosphate; ATP, adenosine triphosphate.

Figure 2

Notch signaling in hematopoiesis. (A) Overview of Notch signaling in hematopoietic cells. Blue gradient represents level of Notch1 expression, red gradient represents level of Notch2 expression, and green gradient represents level of Notch activity as determined using Hes1GFP/WT mice. (B) Notch-deficient hematopoiesis. Genetic inhibition of Notch signaling in HSCs leads to accumulation of GMP, reduction of erythrocyte progenitors, and inhibition of marginal zone B-cell differentiation and T-cell differentiation. CFU-E, colony forming unit-erythrocyte; CLP, common lymphoid progenitors; CMP, common myeloid progenitors; DN3, double-negative 3; ETP, early T-cell progenitors; FoB, follicular B cells; GMP, granulocyte/monocyte progenitors; LMPP, lymphoid-primed multipotent progenitors; LT-HSC, long-term hematopoietic stem cells; MegE, megakaryocyte/erythrocyte progenitors; MkP, megakaryocyte progenitors; MPP, multipotent progenitor; MzB, marginal zone B cell; ProB, pro-B cell; ProE, proerythrocyte.

Figure 3

Mechanisms of Notch signaling silencing in AML. So far, 4 potential levels of silencing of Notch signaling have been identified: (1) AML-initiating cells may reside in niches not expressing Notch ligands; (2) Notch pathway genes might be mutated (so far, only MAML1 mutations have been identified); (3) Notch pathway genes might be epigenetically silenced (for example, HES5, LFNG, and MAML1 have been shown to be hypermethylated in IDH mutant patients; and (4) alternative splicing of Notch pathway genes might lead to expression of inactive isoforms (to date, mis- or alternative-splicing of NOTCH2 and RBP-Jκ have been identified in a large fraction of AML patients).