Understanding the Notch Signaling Pathway in Acute Myeloid Leukemia Stem Cells: From Hematopoiesis to Neoplasia

Abstract

The Notch signaling pathway is fundamental to early fetal development, but its role in acute myeloid leukemia is still unclear. It is important to elucidate the function that contains Notch, not only in acute myeloid leukemia, but in leukemic stem cells (LSCs). LSCs seem to be the principal cause of patient relapse. This population is in a quiescent state. Signaling pathways that govern this process must be understood to increase the chemosensitivity of this compartment. In this review, we focus on the conserved Notch signaling pathway, and its repercussions in hematopoiesis and hematological neoplasia. We found in the literature both visions regarding Notch activity in acute myeloid leukemia. On one hand, the activation of Notch leads to cell proliferation, on the other hand, the activation of Notch leads to cell cycle arrest. This dilemma requires further experiments to be answered, in order to understand the role of Notch not only in acute myeloid leukemia, but especially in LSCs.

Keywords: AML; LSCs; Notch; crosstalk; quiescence.

Figure 1

Notch signaling pathway. The interaction between Delta-like or Jagged-like ligands and NOTCH entails the activation of the signaling pathway. Whereas the extracellular domain (NECD) is split by a disintegrin and metalloproteinase (ADAM), the intracellular domain (NICD) is released by γ-secretase. Therefore, NICD translocates into the nucleus, displacing the co-repressor proteins (CoR) and promoting the target genes with the assistance of co-activators proteins (CoA) and CSL (CBF1/RBPJ-κ, suppressor of Hairless and LAG1). The common therapy target is by inhibiting γ-secretase; these types of drugs are collectively known as Gamma Secretase Inhibitors (GSIs). Nevertheless, blocking monoclonal antibodies (mAbs) is another strategy to inhibit Notch signaling. Figure were created with BioRender.com (accessed on 13 January 2022).