TY - JOUR AU - Gerby, Bastien AU - Veiga, Diogo F.T. AU - Krosl, Jana AU - Nourreddine, Sami AU - Ouellette, Julianne AU - Haman, André AU - Lavoie, Geneviève AU - Fares, Iman AU - Tremblay, Mathieu AU - Litalien, Véronique AU - Ottoni, Elizabeth AU - Kosic, Milena AU - Geoffrion, Dominique AU - Ryan, Joël AU - Maddox, Paul S. AU - Chagraoui, Jalila AU - Marinier, Anne AU - Hébert, Josée AU - Sauvageau, Guy AU - Kwok, Benjamin H. AU - Roux, Philippe P. AU - Hoang, Trang T1 - High-throughput screening in niche-based assay identifies compounds to target preleukemic stem cells PY - 2016/12/01/ AB - 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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI86489 VL - 126 IS - 12 UR - https://doi.org/10.1172/JCI86489 SP - 4569 EP - 4584 PB - The American Society for Clinical Investigation ER -