Notch: From fly wings to human hematological tumors

Leonardo Mirandola, Sara Larocca, Katia Rea, Giovanni Palma, Paola Comi, Raffaella Chiaramonte

Research output: Contribution to journalArticlepeer-review

Abstract

Notch history begins in 1919 with Thomas Hunt Morgan studies on fruit fly mutants. From then, this gene aroused lively interest in the scientific community since it is involved in a wide variety of processes, including morphogenesis, tissue homeostasis, and stem cell maintenance. Deregulation of Notch signaling characterizes several human tumors. Hematopoietic system is affected by mutations of Notch receptors, Notch ligands, and proteins controlling their stability. Approximately 60% T acute lymphoblastic leukemia (T-ALL) patients carry activating Notch1 mutations prompting blasts growth. In addition, multiple myeloma is characterized by Notch signaling hyper-activation due to an abnormal expression of the Jagged2 ligand; this affects not only myeloma cells, but also their interaction with bone marrow microenvironment, influencing tumor burden and bone disease. These findings make Notch a rational target of a therapeutic approach. Inhibitors of the Notch activating enzyme, γ-Secretase, have been successfully used in vitro and in vivo and are currently under clinical trials for T-ALL and breast cancer. Yet a wide use of these inhibitors is prevented by frequently occurring drug resistance. To elucidate the mechanism underlying this phenomenon, a number of pathways have been identified mediating Notch biological effects: AKT and c-Myc are frequently deregulated in leukemic patients and account for resistance to γ-Secretase inhibitors by acting downstream Notch receptor. Therefore, the interaction of Notch with other cancer-associated proteins should be clarified to predict the biological outcome of a Notch targeted therapy and possibly, to exploit combined treatments against the key deregulated elements in Notch-associated cancers.

Original languageEnglish
Pages (from-to)72-77
Number of pages6
JournalArchive of Oncology
Volume17
Issue number3-4
DOIs
Publication statusPublished - Dec 2009

Keywords

  • Amyloid precursor protein secretases
  • Enzyme inhibitors
  • Intracellular signaling peptides and proteins
  • Multiple myeloma
  • Precursor cell lymphoblastic leukemia-lymphoma
  • Proto-oncogene proteins c-akt
  • Proto-oncogene proteins c-myc
  • PTEN phosphohydrolase
  • Receptors, Notch

ASJC Scopus subject areas

  • Oncology
  • Hematology

Fingerprint Dive into the research topics of 'Notch: From fly wings to human hematological tumors'. Together they form a unique fingerprint.

Cite this