2-ME2 selectively targets pre-LSCs by inhibiting MYC translation and SCL activity.

  • Major finding: 2-ME2 selectively targets pre-LSCs by inhibiting MYC translation and SCL activity.

  • Approach: A screen was performed for compounds that selectively target pre-LSCs in a niche-like microenvironment.

  • Impact: Drug screens in tissue-like conditions may enhance the discovery of anticancer therapies.

In patients with T-cell acute lymphoblastic leukemia (T-ALL), the preleukemic stem cell (pre-LSC) population is less proliferative and therefore less sensitive to chemotherapy than leukemic blasts. Therapies targeting the pre-LSCs are desired, but the dependence of these cells on their microenvironment has limited the discovery of drugs in high-throughput screens. Gerby and colleagues developed a niche-based assay for high-throughput screening of compounds targeting pre-LSCs in a tissue-like microenvironment. In this assay, pre-LSCs from a preleukemic transgenic mouse model induced by TAL1 (also known as SCL) and LMO were co-cultured with stromal cells expressing the NOTCH1 ligand delta-like 4 (DL4). A library of 1,904 compounds was screened, and the microtubule-targeting drug 2-methoxyestradiol (2-ME2) was identified as a selective inhibitor of pre-LSCs. 2-ME2 blocked the self-renewing capacity of pre-LSCs in vitro and reduced the frequency of pre-LSCs in vivo, and further killed leukemic blasts without affecting normal hematopoietic stem/progenitor cells. Mechanistically, 2-ME2 reduced the nuclear accumulation and transcriptional activity of the transcription factor TAL1 and also blocked translation of MYC, resulting in reduced MYC protein expression, collectively leading to reduced pre-LSC viability. In primary T-ALL cells, 2-ME2 treatment reduced cell viability in a dose-dependent manner and decreased expression of TAL1 and MYC proteins. In vivo, 2-ME2 reduced the leukemic burden in two patient-derived T-ALL xenografts and downregulated TAL1 and MYC. In addition to finding that 2-ME2 selectively targets T-ALL pre-LSCs, these results indicate that performing high-throughput screens in niche-based assays that recapitulate the microenvironment may improve drug discovery and lead to the identification of new therapies.

Gerby B, Veiga DF, Krosl J, Nourreddine S, Ouellette J, Haman A, et al. High-throughput screening in niche-based assay identifies compounds to target preleukemic stem cells. J Clin Invest 2016 Oct 31 [Epub ahead of print].