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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.

SUBMITTER: Gerby B

PROVIDER: S-EPMC5127686 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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High-throughput screening in niche-based assay identifies compounds to target preleukemic stem cells.

Gerby Bastien B Veiga Diogo F T DF Krosl Jana J Nourreddine Sami S Ouellette Julianne J Haman André A Lavoie Geneviève G Fares Iman I Tremblay Mathieu M Litalien Véronique V Ottoni Elizabeth E Kosic Milena M Geoffrion Dominique D Ryan Joël J Maddox Paul S PS Chagraoui Jalila J Marinier Anne A Hébert Josée J Sauvageau Guy G Kwok Benjamin H BH Roux Philippe P PP Hoang Trang T

The Journal of clinical investigation 20161031 12

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 ...[more]

PMID: 27797342

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Dataset Information

High-throughput screening in niche-based assay identifies compounds to target preleukemic stem cells.

Publications

High-throughput screening in niche-based assay identifies compounds to target preleukemic stem cells.

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