title: AMP-dependent kinase/mammalian target of rapamycin complex 1 signaling in T-cell acute lymphoblastic leukemia: therapeutic implications.
abstract: The mammalian target of rapamycin (mTOR) serine/threonine kinase is the catalytic subunit of two multi-protein complexes, referred to as mTORC1 and mTORC2. Signaling downstream of mTORC1 has a critical role in leukemic cell biology by controlling mRNA translation of genes involved in both cell survival and proliferation. mTORC1 activity can be downmodulated by upregulating the liver kinase B1/AMP-activated protein kinase (LKB1/AMPK) pathway. Here, we have explored the therapeutic potential of the anti-diabetic drug, metformin (an LKB1/AMPK activator), against both T-cell acute lymphoblastic leukemia (T-ALL) cell lines and primary samples from T-ALL patients displaying mTORC1 activation. Metformin affected T-ALL cell viability by inducing autophagy and apoptosis. However, it was much less toxic against proliferating CD4(+) T-lymphocytes from healthy donors. Western blot analysis demonstrated dephosphorylation of mTORC1 downstream targets. Unlike rapamycin, we found a marked inhibition of mRNA translation in T-ALL cells treated with metformin. Remarkably, metformin targeted the side population of T-ALL cell lines as well as a putative leukemia-initiating cell subpopulation (CD34(+)/CD7(-)/CD4(-)) in patient samples. In conclusion, metformin displayed a remarkable anti-leukemic activity, which emphasizes future development of LKB1/AMPK activators as clinical candidates for therapy in T-ALL.
authors.affiliation: Department of Human Anatomy, University of Bologna, Bologna, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Grimaldi
authors.forename: F
authors.initials: F
authors.lastname: Chiarini
authors.forename: G
authors.initials: G
authors.lastname: Tabellini
authors.forename: F
authors.initials: F
authors.lastname: Ricci
authors.forename: P L
authors.initials: PL
authors.lastname: Tazzari
authors.forename: M
authors.initials: M
authors.lastname: Battistelli
authors.forename: E
authors.initials: E
authors.lastname: Falcieri
authors.forename: R
authors.initials: R
authors.lastname: Bortul
authors.forename: F
authors.initials: F
authors.lastname: Melchionda
authors.forename: I
authors.initials: I
authors.lastname: Iacobucci
authors.forename: P
authors.initials: P
authors.lastname: Pagliaro
authors.forename: G
authors.initials: G
authors.lastname: Martinelli
authors.forename: A
authors.initials: A
authors.lastname: Pession
authors.forename: J T
authors.initials: JT
authors.lastname: Barata
authors.forename: J A
authors.initials: JA
authors.lastname: McCubrey
authors.forename: A M
authors.initials: AM
authors.lastname: Martelli
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism*; D017209:Apoptosis; D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D005434:Flow Cytometry; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D008687:Metformin / Q000494:pharmacology; D046912:Multiprotein Complexes; D010766:Phosphorylation; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism* / Q000473:pathology; D014176:Protein Biosynthesis / Q000187:drug effects; D011506:Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
chemical_list: D017931:DNA Primers; D046912:Multiprotein Complexes; D011506:Proteins; D012333:RNA, Messenger; D008687:Metformin; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D000263:Adenylate Kinase