Abstract
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.
