A small molecule screening strategy with validation on human leukemia stem cells uncovers the therapeutic efficacy of kinetin riboside.

Abstract

Gene regulatory networks that govern hematopoietic stem cells (HSCs) and leukemia-initiating cells (L-ICs) are deeply entangled. Thus, the discovery of compounds that target L-ICs while sparing HSC is an attractive but difficult endeavor. Presently, most screening approaches fail to counter-screen compounds against normal hematopoietic stem/progenitor cells (HSPCs). Here, we present a multistep in vitro and in vivo approach to identify compounds that can target L-ICs in acute myeloid leukemia (AML). A high-throughput screen of 4000 compounds on novel leukemia cell lines derived from human experimental leukemogenesis models yielded 80 hits, of which 10 were less toxic to HSPC. We characterized a single compound, kinetin riboside (KR), on AML L-ICs and HSPCs. KR demonstrated comparable efficacy to standard therapies against blast cells in 63 primary leukemias. In vitro, KR targeted the L-IC-enriched CD34(+)CD38(-) AML fraction, while sparing HSPC-enriched fractions, although these effects were mitigated on HSC assayed in vivo. KR eliminated L-ICs in 2 of 4 primary AML samples when assayed in vivo and highlights the importance of in vivo L-IC and HSC assays to measure function. Overall, we provide a novel approach to screen large drug libraries for the discovery of anti-L-IC compounds for human leukemias.

• Authors: Sean P McDermott, Kolja Eppert, Faiyaz Notta, Methvin Isaac, Alessandro Datti, Rima Al-Awar, Jeff Wrana, Mark D Minden, John E Dick
• Journal: Blood (Blood) Vol. 119 Issue 5 Pg. 1200-7 (Feb 02 2012) ISSN: 1528-0020 [Electronic] United States
• PMID: 22160482 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Validation Study)

Chemical References

• Antineoplastic Agents
• Small Molecule Libraries
• kinetin riboside
• Adenosine
• Kinetin

Topics

• Adenosine (analysis, isolation & purification, pharmacology, therapeutic use)
• Animals
• Antineoplastic Agents (analysis, isolation & purification, pharmacology, therapeutic use)
• High-Throughput Screening Assays (methods)
• Humans
• Kinetin (analysis, isolation & purification, pharmacology, therapeutic use)
• Leukemia (drug therapy, pathology)
• Mice
• Mice, Inbred NOD
• Mice, Nude
• Mice, SCID
• Neoplastic Stem Cells (drug effects, pathology)
• Small Molecule Libraries (analysis)
• Treatment Outcome
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays