Niche-based Screening Identifies Small-molecule Inhibitors of Leukemia Stem Cells

Overview

Journal Nat Chem Biol

Specialties Biochemistry
Biology
Chemistry

Date 2013 Oct 29

PMID 24161946

Citations 65

Authors

Kimberly A Hartwell

Peter G Miller

Siddhartha Mukherjee

Alissa R Kahn

Alison L Stewart

David J Logan

Joseph M Negri

Mildred Duvet

Marcus Jaras

Rishi Puram

Vlado Dancik

Fatima Al-Shahrour

Thomas Kindler

Zuzana Tothova

Shrikanta Chattopadhyay

Thomas Hasaka

Rajiv Narayan

Mingji Dai

Christina Huang

Sebastian Shterental

Lisa P Chu

J Erika Haydu

Jae Hung Shieh

David P Steensma

Benito Munoz

Joshua A Bittker

Alykhan F Shamji

Paul A Clemons

Nicola J Tolliday

Anne E Carpenter

D Gary Gilliland

Andrew M Stern

Malcolm A S Moore

David T Scadden

Stuart L Schreiber

Benjamin L Ebert

Todd R Golub

Affiliations

Soon will be listed here.

Abstract

Efforts to develop more effective therapies for acute leukemia may benefit from high-throughput screening systems that reflect the complex physiology of the disease, including leukemia stem cells (LSCs) and supportive interactions with the bone marrow microenvironment. The therapeutic targeting of LSCs is challenging because LSCs are highly similar to normal hematopoietic stem and progenitor cells (HSPCs) and are protected by stromal cells in vivo. We screened 14,718 compounds in a leukemia-stroma co-culture system for inhibition of cobblestone formation, a cellular behavior associated with stem-cell function. Among those compounds that inhibited malignant cells but spared HSPCs was the cholesterol-lowering drug lovastatin. Lovastatin showed anti-LSC activity in vitro and in an in vivo bone marrow transplantation model. Mechanistic studies demonstrated that the effect was on target, via inhibition of HMG-CoA reductase. These results illustrate the power of merging physiologically relevant models with high-throughput screening.

Citing Articles

Remodeling of the bone marrow microenvironment during acute myeloid leukemia progression.

Urs A, Goda C, Kulkarni R Ann Transl Med. 2024; 12(4):63.

PMID: 39118939 PMC: 11304419. DOI: 10.21037/atm-23-1824.

A CD36-dependent non-canonical lipid metabolism program promotes immune escape and resistance to hypomethylating agent therapy in AML.

Guo H, Feng R, Zhang Y, Yu Y, Lu W, Liu J Cell Rep Med. 2024; 5(6):101592.

PMID: 38843841 PMC: 11228649. DOI: 10.1016/j.xcrm.2024.101592.

The RORɣ/SREBP2 pathway is a master regulator of cholesterol metabolism and serves as potential therapeutic target in t(4;11) leukemia.

Erkner E, Hentrich T, Schairer R, Fitzel R, Secker-Grob K, Jeong J Oncogene. 2023; 43(4):281-293.

PMID: 38030791 PMC: 10798886. DOI: 10.1038/s41388-023-02903-3.

Skin mesenchymal niches maintain and protect AML-initiating stem cells.

Sandhow L, Cai H, Leonard E, Xiao P, Tomaipitinca L, Mansson A J Exp Med. 2023; 220(10).

PMID: 37516911 PMC: 10373345. DOI: 10.1084/jem.20220953.

In Vitro and In Vivo Modeling of Normal and Leukemic Bone Marrow Niches: Cellular Senescence Contribution to Leukemia Induction and Progression.

Salazar-Terreros M, Vernot J Int J Mol Sci. 2022; 23(13).

PMID: 35806354 PMC: 9266537. DOI: 10.3390/ijms23137350.

References

Berndt N, Hamilton A, Sebti S . Targeting protein prenylation for cancer therapy. Nat Rev Cancer. 2011; 11(11):775-91. PMC: 4037130. DOI: 10.1038/nrc3151. View

McMillin D, Delmore J, Weisberg E, Negri J, Geer D, Klippel S . Tumor cell-specific bioluminescence platform to identify stroma-induced changes to anticancer drug activity. Nat Med. 2010; 16(4):483-9. PMC: 3786785. DOI: 10.1038/nm.2112. View

Stentoft J . The toxicity of cytarabine. Drug Saf. 1990; 5(1):7-27. DOI: 10.2165/00002018-199005010-00003. View

Williams A, Li L, Nguyen B, Brown P, Levis M, Small D . Fluvastatin inhibits FLT3 glycosylation in human and murine cells and prolongs survival of mice with FLT3/ITD leukemia. Blood. 2012; 120(15):3069-79. PMC: 3471516. DOI: 10.1182/blood-2012-01-403493. View

Hassane D, Guzman M, Corbett C, Li X, Abboud R, Young F . Discovery of agents that eradicate leukemia stem cells using an in silico screen of public gene expression data. Blood. 2008; 111(12):5654-62. PMC: 2424160. DOI: 10.1182/blood-2007-11-126003. View

Somervaille T, Cleary M . Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia. Cancer Cell. 2006; 10(4):257-68. DOI: 10.1016/j.ccr.2006.08.020. View

Sachlos E, Risueno R, Laronde S, Shapovalova Z, Lee J, Russell J . Identification of drugs including a dopamine receptor antagonist that selectively target cancer stem cells. Cell. 2012; 149(6):1284-97. DOI: 10.1016/j.cell.2012.03.049. View

Guzman M, Rossi R, Karnischky L, Li X, Peterson D, Howard D . The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells. Blood. 2005; 105(11):4163-9. PMC: 1895029. DOI: 10.1182/blood-2004-10-4135. View

Lobell R, Omer C, Abrams M, Bhimnathwala H, Brucker M, Buser C . Evaluation of farnesyl:protein transferase and geranylgeranyl:protein transferase inhibitor combinations in preclinical models. Cancer Res. 2001; 61(24):8758-68. View

10.

Naveiras O, Nardi V, Wenzel P, Hauschka P, Fahey F, Daley G . Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature. 2009; 460(7252):259-63. PMC: 2831539. DOI: 10.1038/nature08099. View

11.

Plosker G, Faulds D . Epirubicin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in cancer chemotherapy. Drugs. 1993; 45(5):788-856. DOI: 10.2165/00003495-199345050-00011. View

12.

Osmak M . Statins and cancer: current and future prospects. Cancer Lett. 2012; 324(1):1-12. DOI: 10.1016/j.canlet.2012.04.011. View

13.

Costello R, Mallet F, Gaugler B, Sainty D, Arnoulet C, Gastaut J . Human acute myeloid leukemia CD34+/CD38- progenitor cells have decreased sensitivity to chemotherapy and Fas-induced apoptosis, reduced immunogenicity, and impaired dendritic cell transformation capacities. Cancer Res. 2000; 60(16):4403-11. View

14.

Weiss R . The anthracyclines: will we ever find a better doxorubicin?. Semin Oncol. 1992; 19(6):670-86. View

15.

Luo B, Cheung H, Subramanian A, Sharifnia T, Okamoto M, Yang X . Highly parallel identification of essential genes in cancer cells. Proc Natl Acad Sci U S A. 2008; 105(51):20380-5. PMC: 2629277. DOI: 10.1073/pnas.0810485105. View

16.

Memon R, Tecott L, Nonogaki K, Beigneux A, MOSER A, Grunfeld C . Up-regulation of peroxisome proliferator-activated receptors (PPAR-alpha) and PPAR-gamma messenger ribonucleic acid expression in the liver in murine obesity: troglitazone induces expression of PPAR-gamma-responsive adipose tissue-specific genes in.... Endocrinology. 2000; 141(11):4021-31. DOI: 10.1210/endo.141.11.7771. View

17.

Langdon W . FLT3 signaling and the development of inhibitors that target FLT3 kinase activity. Crit Rev Oncog. 2012; 17(2):199-209. DOI: 10.1615/critrevoncog.v17.i2.50. View

18.

Huntly B, Shigematsu H, Deguchi K, Lee B, Mizuno S, Duclos N . MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors. Cancer Cell. 2004; 6(6):587-96. DOI: 10.1016/j.ccr.2004.10.015. View

19.

Moore M, Dorn D, Schuringa J, Chung K, Morrone G . Constitutive activation of Flt3 and STAT5A enhances self-renewal and alters differentiation of hematopoietic stem cells. Exp Hematol. 2007; 35(4 Suppl 1):105-16. DOI: 10.1016/j.exphem.2007.01.018. View

20.

Guzman M, Rossi R, Neelakantan S, Li X, Corbett C, Hassane D . An orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells. Blood. 2007; 110(13):4427-35. PMC: 2234793. DOI: 10.1182/blood-2007-05-090621. View