High-throughput screening in niche-based assay identifies compounds to target preleukemic stem cells

被引：31

作者：

Gerby, Bastien ^{[1
,2
]}

Veiga, Diogo F. T. ^{[1
,2
,7
]}

Krosl, Jana ^{[1
]}

Nourreddine, Sami ^{[1
,2
]}

Ouellette, Julianne ^{[1
,2
]}

Haman, Andre ^{[1
,2
]}

Lavoie, Genevieve ^{[1
,2
]}

Fares, Iman ^{[1
]}

Tremblay, Mathieu ^{[1
,2
,8
]}

Litalien, Veronique ^{[1
]}

Ottoni, Elizabeth ^{[1
,2
]}

Kosic, Milena ^{[1
,2
,9
]}

Geoffrion, Dominique ^{[1
,2
]}

Ryan, Joel ^{[1
]}

Maddox, Paul S. ^{[3
]}

Chagraoui, Jalila ^{[1
]}

Marinier, Anne ^{[1
]}

Hebert, Josee ^{[4
]}

Sauvageau, Guy ^{[1
,4
]}

Kwok, Benjamin H. ^{[1
,2
]}

Roux, Philippe P. ^{[1
,2
]}

Hoang, Trang ^{[1
,2
,5
,6
]}

机构：

[1] Univ Montreal, Fac Med, Inst Res Immunol & Canc, Montreal, PQ, Canada

[2] Univ Montreal, Fac Med, Mol Biol Program, Montreal, PQ, Canada

[3] Univ North Carolina Chapel Hill, Dept Biol, Chapel Hill, NC USA

[4] Maisonneuve Rosemont Hosp, Leukemia Cell Bank Quebec, Dept Med, Montreal, PQ, Canada

[5] Univ Montreal, Fac Med, Dept Pharmacol & Physiol, Montreal, PQ, Canada

[6] Univ Montreal, Fac Med, Dept Biochem, Montreal, PQ, Canada

[7] Jackson Lab Genom Med, Farmington, CT USA

[8] McGill Canc Ctr, Montreal, PQ, Canada

[9] Univ Toronto, Fac Pharm, Dept Pharmaceut Sci, Toronto, ON, Canada

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2016年 / 126卷 / 12期

基金：

加拿大创新基金会;

关键词：

ACUTE LYMPHOBLASTIC-LEUKEMIA; ACUTE MYELOID-LEUKEMIA; HEMATOPOIETIC STEM; C-MYC; SELF-RENEWAL; PROGENITOR CELLS; BONE-MARROW; LINEAGE COMMITMENT; TRANSGENIC MICE; PHASE-I;

D O I：

10.1172/JCI86489

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Current chemotherapies for T cell acute lymphoblastic leukemia (T-ALL) efficiently reduce tumor mass. Nonetheless, disease relapse attributed to survival of preleukemic stem cells (pre-LSCs) is associated with poor prognosis. Herein, we provide direct evidence that pre-LSCs are much less chemosensitive to existing chemotherapy drugs than leukemic blasts because of a distinctive lower proliferative state. Improving therapies for T-ALL requires the development of strategies to target pre-LSCs that are absolutely dependent on their microenvironment. Therefore, we designed a robust protocol for high-throughput screening of compounds that target primary pre-LSCs maintained in a niche-like environment, on stromal cells that were engineered for optimal NOTCH1 activation. The multiparametric readout takes into account the intrinsic complexity of primary cells in order to specifically monitor pre-LSCs, which were induced here by the SCL/TAL1 and LMO1 oncogenes. We screened a targeted library of compounds and determined that the estrogen derivative 2-methoxyestradiol (2-ME2) disrupted both cell-autonomous and non-cell-autonomous pathways. Specifically, 2-ME2 abrogated pre-LSC viability and self-renewal activity in vivo by inhibiting translation of MYC, a downstream effector of NOTCH1, and preventing SCL/TAL1 activity. In contrast, normal hematopoietic stem/progenitor cells remained functional. These results illustrate how recapitulating tissue-like properties of primary cells in high-throughput screening is a promising avenue for innovation in cancer chemotherapy.

引用

页码：4569 / 4584

页数：16