Abstract
A high-throughput screen identified compounds that selectively inhibit AML LSCs but spare HSPCs.
Major finding: A high-throughput screen identified compounds that selectively inhibit AML LSCs but spare HSPCs.
Mechanism: Lovastatin inhibits LSCs via HMGCR blockade, whereas other compounds target stromal cells.
Impact: Small-molecule screens that model LSCs in the bone marrow niche may suggest new AML therapies.
Efforts to develop agents that specifically target leukemic stem cells (LSC) have been hampered by toxicity in normal hematopoietic stem and progenitor cells (HSPC) and by the inability to model the interaction of LSCs with supportive stromal cells in the bone marrow microenvironment in high-throughput screens. To overcome these limitations, Hartwell and colleagues developed a coculture-based system consisting of bone marrow–derived stromal cells and LSC-enriched cells from a mouse model of acute myeloid leukemia (AML) or primary human AML samples and used an automated algorithm to measure the ability of LSCs to form cobblestone areas, a morphologic phenotype characteristic of stem-cell function, in the context of this simulated niche. A large panel of small molecules was then screened to identify compounds that inhibited LSC cobblestone formation but did not induce stromal-cell or normal HSPC toxicity, yielding 155 compounds including several molecules known to target LSCs. Of note, a subset of these compounds was not detected in conventional screens of human AML cell lines, underscoring the utility of the coculture screening approach. Among the newly identified compounds, a bis-aryl sulfone, BRD7116, inhibited LSCs via non–cell-autonomous effects on stromal cells as well as cell-autonomous induction of myeloid differentiation genes in LSCs. In addition, lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the rate-limiting enzyme in cholesterol biosynthesis, exhibited LSC-selective activity against both cocultured mouse LSCs and patient-derived AML cells via on-target inhibition of HMGCR. Moreover, treatment with lovastatin suppressed LSC-induced leukemia initiation and prolonged survival in bone marrow transplantation assays without affecting normal HSPC engraftment. These findings suggest that inhibition of the mevalonate pathway using statins may be an effective therapeutic strategy to preferentially target LSCs in AML and validate the physiologic relevance of this high-throughput approach.
RSS Feeds