title: Targeting signaling pathways in T-cell acute lymphoblastic leukemia initiating cells.
abstract: Leukemia initiating cells (LICs) represent a reservoir that is believed to drive relapse and resistance to chemotherapy in blood malignant disorders. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive neoplastic disorder of immature hematopoietic precursors committed to the T-cell lineage. T-ALL comprises about 15% of pediatric and 25% of adult ALL cases and is prone to early relapse. Although the prognosis of T-ALL has improved especially in children due to the use of new intensified treatment protocols, the outcome of relapsed T-ALL cases is still poor. Putative LICs have been identified also in T-ALL. LICs are mostly quiescent and for this reason highly resistant to chemotherapy. Therefore, they evade treatment and give rise to disease relapse. At present great interest surrounds the development of targeted therapies against signaling networks aberrantly activated in LICs and important for their survival and drug-resistance. Both the Notch1 pathway and the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) network are involved in T-ALL LIC survival and drug-resistance and could be targeted by small molecules. Thus, Notch1 and PI3K/Akt/mTOR inhibitors are currently being developed for clinical use either as single agents or in combination with conventional chemotherapy for T-ALL patient treatment. In this review, we summarize the existing knowledge of the relevance of Notch1 and PI3K/Akt/mTOR signaling in T-ALL LICs and we examine the rationale for targeting these key signal transduction networks by means of selective pharmacological inhibitors.
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, via Irnerio 48, 40126 Bologna, Italy. Electronic address: alberto.martelli@unibo.it.
authors.forename: Alberto M
authors.initials: AM
authors.lastname: Martelli
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, via Irnerio 48, 40126 Bologna, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Lonetti
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, via Irnerio 48, 40126 Bologna, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Buontempo
authors.affiliation: Immunohematology and Transfusion Center, Policlinico S.Orsola-Malpighi, Bologna, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Ricci
authors.affiliation: Immunohematology and Transfusion Center, Policlinico S.Orsola-Malpighi, Bologna, Italy.
authors.forename: Pier Luigi
authors.initials: PL
authors.lastname: Tazzari
authors.affiliation: Institute of Molecular Genetics, National Research Council, via di Barbiano 1/10, 40136 Bologna, Italy; Musculoskeletal Cell Biology Laboratory, IOR, via di Barbiano 1/10, 40136 Bologna, Italy.
authors.forename: Camilla
authors.initials: C
authors.lastname: Evangelisti
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, via Irnerio 48, 40126 Bologna, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Bressanin
authors.affiliation: Department of Human, Social and Health Sciences, University of Cassino, 03043 Cassino, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cappellini
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, via Irnerio 48, 40126 Bologna, Italy.
authors.forename: Ester
authors.initials: E
authors.lastname: Orsini
authors.affiliation: Institute of Molecular Genetics, National Research Council, via di Barbiano 1/10, 40136 Bologna, Italy; Musculoskeletal Cell Biology Laboratory, IOR, via di Barbiano 1/10, 40136 Bologna, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Chiarini
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D006801:Humans; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: Notch1; PI3K/Akt/mTOR; Relapse; T-ALL; Targeted therapy