title: High-throughput screening in niche-based assay identifies compounds to target preleukemic stem cells.
abstract: Current chemotherapies for T cell acute lymphoblastic leukemia (T-ALL) efficiently reduce tumor mass. Nonetheless, disease relapse attributed to survival of preleukemic stem cells (pre-LSCs) is associated with poor prognosis. Herein, we provide direct evidence that pre-LSCs are much less chemosensitive to existing chemotherapy drugs than leukemic blasts because of a distinctive lower proliferative state. Improving therapies for T-ALL requires the development of strategies to target pre-LSCs that are absolutely dependent on their microenvironment. Therefore, we designed a robust protocol for high-throughput screening of compounds that target primary pre-LSCs maintained in a niche-like environment, on stromal cells that were engineered for optimal NOTCH1 activation. The multiparametric readout takes into account the intrinsic complexity of primary cells in order to specifically monitor pre-LSCs, which were induced here by the SCL/TAL1 and LMO1 oncogenes. We screened a targeted library of compounds and determined that the estrogen derivative 2-methoxyestradiol (2-ME2) disrupted both cell-autonomous and non-cell-autonomous pathways. Specifically, 2-ME2 abrogated pre-LSC viability and self-renewal activity in vivo by inhibiting translation of MYC, a downstream effector of NOTCH1, and preventing SCL/TAL1 activity. In contrast, normal hematopoietic stem/progenitor cells remained functional. These results illustrate how recapitulating tissue-like properties of primary cells in high-throughput screening is a promising avenue for innovation in cancer chemotherapy.
authors: Bastien
authors: B
authors: Gerby
authors: Diogo F T
authors: DF
authors: Veiga
authors: Jana
authors: J
authors: Krosl
authors: Sami
authors: S
authors: Nourreddine
authors: Julianne
authors: J
authors: Ouellette
authors: André
authors: A
authors: Haman
authors: Geneviève
authors: G
authors: Lavoie
authors: Iman
authors: I
authors: Fares
authors: Mathieu
authors: M
authors: Tremblay
authors: Véronique
authors: V
authors: Litalien
authors: Elizabeth
authors: E
authors: Ottoni
authors: Milena
authors: M
authors: Kosic
authors: Dominique
authors: D
authors: Geoffrion
authors: Joël
authors: J
authors: Ryan
authors: Paul S
authors: PS
authors: Maddox
authors: Jalila
authors: J
authors: Chagraoui
authors: Anne
authors: A
authors: Marinier
authors: Josée
authors: J
authors: Hébert
authors: Guy
authors: G
authors: Sauvageau
authors: Benjamin H
authors: BH
authors: Kwok
authors: Philippe P
authors: PP
authors: Roux
authors: Trang
authors: T
authors: Hoang
mesh_terms: D000077584:2-Methoxyestradiol; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D019169:Jurkat Cells; D060588:LIM Domain Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D059016:Tumor Microenvironment / Q000187:drug effects* / Q000235:genetics; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
chemical_list: D000077584:2-Methoxyestradiol; D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D004958:Estradiol; D060588:LIM Domain Proteins; D011518:Proto-Oncogene Proteins; D051881:Receptor, Notch1; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors; C065072:LMO1 protein, human; C497761:NOTCH1 protein, human; C067143:TAL1 protein, human