title: Inhibition of serotonin receptor type 1 in acute myeloid leukemia impairs leukemia stem cell functionality: a promising novel therapeutic target.
abstract: Acute myeloid leukemia (AML) is a clinically and molecularly heterogeneous neoplasia with poor outcome, organized as a hierarchy initiated and maintained by a sub-population with differentiation and self-renewal capacities called leukemia stem cells (LSCs). Although currently used chemotherapy is capable of initially reducing the tumor burden producing a complete remission, most patients will ultimately relapse and will succumb to their disease. As such, new therapeutic strategies are needed. AML cells differentially expressed serotonin receptor type 1 (HTR1) compared with healthy blood cells and the most primitive hematopoietic fraction; in fact, HTR1B expression on AML patient samples correlated with clinical outcome. Inhibition of HTR1s activated the apoptosis program, induced differentiation and reduced the clonogenic capacity, while minimal effect was observed on healthy blood cells. In vivo regeneration capacity of primary AML samples was disrupted upon inhibition of HTR1. The self-renewal capacity remaining in AML cells upon in vivo treatment was severely reduced as demonstrated by serial transplantation. Thus, treatment with HTR1 antagonists showed antileukemia effect, especially anti-LSC activity while sparing healthy blood cells. Our results highlight the importance of HTR1 in leukemogenesis and LSC survival and identify this receptor family as a new target for therapy in AML with prognostic value.
authors.affiliation: Josep Carreras Leukaemia Research Institute, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Etxabe
authors.affiliation: Josep Carreras Leukaemia Research Institute, Barcelona, Spain.
authors.forename: M C
authors.initials: MC
authors.lastname: Lara-Castillo
authors.affiliation: Josep Carreras Leukaemia Research Institute, Barcelona, Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: Cornet-Masana
authors.affiliation: Josep Carreras Leukaemia Research Institute, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Banús-Mulet
authors.affiliation: Josep Carreras Leukaemia Research Institute, Barcelona, Spain.|Department of Hematology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Nomdedeu
authors.affiliation: Josep Carreras Leukaemia Research Institute, Barcelona, Spain.|Department of Hematology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: M A
authors.initials: MA
authors.lastname: Torrente
authors.affiliation: Josep Carreras Leukaemia Research Institute, Barcelona, Spain.|Department of Hematology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Pratcorona
authors.affiliation: Department of Hematology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|University of Barcelona, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Díaz-Beyá
authors.affiliation: Josep Carreras Leukaemia Research Institute, Barcelona, Spain.|Department of Hematology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|University of Barcelona, Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Esteve
authors.affiliation: Josep Carreras Leukaemia Research Institute, Barcelona, Spain.
authors.forename: R M
authors.initials: RM
authors.lastname: Risueño
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D003561:Cytarabine / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000473:pathology*; D044263:Receptors, Serotonin, 5-HT1 / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D003561:Cytarabine