• Role of Notch Signaling in Acute Leukemia Stem Cells
  • Zahra Ranjbarpoor,1,*
    1. Msc of Molecular Genetic Department of Genetics, Zanjan Branch, Islamic Azad University, Zanjan, Iran.


  • Introduction: Leukemia is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called blasts or leukemia cells. Notch has an important role in several functions related to embryogenesis and cell fate in adult tissues. Indeed, Notch signaling has been extensively linked to both processes of normal and malignant stem cell (SC) self-renewal. For this reason, it is important to comprehend its implications not only in its physiological form, but also in its aberrant variety. Our objective with this review is to summarize the available information about the hematological role of Notch, mainly in the regulation of the leukemic stem cells (LSCs) of acute myeloid leukemia (AML). In this paper, we also examine the interdependence of Notch signaling with Hedgehog (Hh) and Wnt. These 3 pathways are connected during embryo development, but also in SC regulation and differentiation in different tissues. The aim of this study was to investigate the role of Notch Signaling in Acute Leukemia Stem Cells.
  • Methods: This study used scientific databases including Science Direct, Springer, Google Scholar, and PubMed.
  • Results: Results showed A The important role of Notch in embryos was described by Robert-Moreno et al. when they studied Notch1 mutation in mouse embryos. They showed that a mutation in this gene entails deficiencies in intra-embryonic hematopoiesis. In adults, Notch has a crucial position in hematopoiesis: its inhibition can alter hematopoietic linages due to its importance in cell fate. Indeed, Notch1 has a major role in adult hematopoiesis by controlling events, such as lymphoid vs. myeloid differentiation, T vs. B lymphoid fate, αβ vs. γδ T-cell fate, and possibly CD4 vs. CD8 T-cell lineages. Furthermore, Notch, certainly Notch1 , is needed for the expansion of the hematopoietic stem cell (HSC) compartment. Almost 60% of patients with T-cell acute lymphoblastic leukemia (T-ALL) have mutations of NOTCH1 , but the prognosis of this mutation is not clear and seems to be dependent on additional genetic lesions. The high ratio of mutations in this gene suggest that T-ALL is the hematological neoplasia most closely related to this signaling pathway. In this neoplasia, NOTCH3 promotes JAG1, a phenomenon that is caused by a NOTCH3/JAG1 auto sustaining loop. This mechanism would produce a positive auto feedback and a stimulant paracrine effect in the adjacent cells. The loop seems to support the survival, proliferation, and invasion of leukemic cells and contributes to the development and progression of T-ALL. Moreover, this signaling pathway could have prognostic value in those patients suffering from chronic lymphocytic leukemia (CLL). There are multiple studies that support NOTCH1 mutations as a negative predictor factor of CLL patients. Indeed, some authors found NOTCH1 mutated in 11% of CLL patients and found that mutations in this gene are in 90% of the cases mutually exclusive with TP53 disruptions, and confer a similarly dismal prognosis with a reduction in the overall survival (OS). Therefore, the role of Notch seems fundamental for lymphoid neoplasia.
  • Conclusion: In order to exploit the therapeutic potential of the Notch pathway, firstly, we believe it is essential to decipher the role of Notch in the regulation of the quiescence of the LSC population. Single-cell technologies might help us in this difficult task. In a further step, targeted therapies could be employed, either directed only towards Notch or also directed towards Hh and/or Wnt, alongside conventional chemotherapy. This therapeutic strategy could decrease the quiescence of LSCs, increase their chemo sensibility and achieve the eradication of LSCs and AML curation.
  • Keywords: Notch Signaling, Acute Leukemia, Stem Cells