Niche-based screening identifies small-molecule inhibitors of leukemia stem cells

被引：1

作者：

Hartwell, Kimberly A. ^{[1
,2
,3
]}

Miller, Peter G. ^{[2
,3
]}

Mukherjee, Siddhartha ^{[4
,5
]}

Kahn, Alissa R. ^{[6
]}

Stewart, Alison L. ^{[1
]}

Logan, David J. ^{[1
]}

Negri, Joseph M. ^{[1
]}

Duvet, Mildred ^{[1
,4
,5
]}

Jaeras, Marcus ^{[2
,3
]}

Puram, Rishi ^{[2
,3
]}

Dancik, Vlado ^{[1
]}

Al-Shahrour, Fatima ^{[1
,2
,3
]}

Kindler, Thomas ^{[2
,3
]}

Tothova, Zuzana ^{[2
,3
]}

Chattopadhyay, Shrikanta ^{[1
,7
]}

Hasaka, Thomas ^{[1
]}

Narayan, Rajiv ^{[1
]}

Dai, Mingji ^{[1
,8
]}

Huang, Christina ^{[1
]}

Shterental, Sebastian ^{[2
,3
]}

Chu, Lisa P. ^{[2
,3
]}

Haydu, J. Erika ^{[2
,3
]}

Shieh, Jae Hung ^{[6
]}

Steensma, David P. ^{[3
,9
]}

Munoz, Benito ^{[1
]}

Bittker, Joshua A. ^{[1
]}

Shamji, Alykhan F. ^{[1
]}

Clemons, Paul A. ^{[1
]}

Tolliday, Nicola J. ^{[1
]}

Carpenter, Anne E. ^{[1
]}

Gilliland, D. Gary ^{[1
,2
,3
,9
,10
]}

Stern, Andrew M. ^{[1
]}

Moore, Malcolm A. S. ^{[11
]}

Scadden, David T. ^{[1
,4
,5
,7
]}

Schreiber, Stuart L. ^{[1
,8
,10
]}

Ebert, Benjamin L. ^{[1
,2
,3
,9
]}

Golub, Todd R. ^{[1
,3
,10
,12
]}

机构：

[1] Broad Inst, Cambridge, MA 02142 USA

[2] Brigham & Womens Hosp, Dept Med, Div Hematol, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Boston, MA USA

[4] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA

[5] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA

[6] Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10021 USA

[7] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA

[8] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA

[9] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[10] Harvard Univ, Howard Hughes Med Inst, Sch Med, Chevy Chase, MD USA

[11] Mem Sloan Kettering Canc Ctr, Cell Biol Program, New York, NY 10021 USA

[12] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

来源：

NATURE CHEMICAL BIOLOGY | 2013年 / 9卷 / 12期

基金：

美国国家科学基金会; 美国国家卫生研究院;

关键词：

ACUTE MYELOID-LEUKEMIA; PROGENITOR CELLS; STROMAL CELLS; PROTEIN TRANSFERASE; FREQUENCY-ANALYSIS; INDUCED APOPTOSIS; IN-VIVO; CANCER; GENES; MICE;

D O I：

10.1038/NCHEMBIO.1367

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：840 / +

页数：12

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