Single-Cell RNA-Seq Reveals AML Hierarchies Relevant to Disease Progression and Immunity

被引：732

作者：

van Galen, Peter ^{[1
,2
,3
,4
,5
]}

Hovestadt, Volker ^{[1
,2
,3
,4
,5
]}

Wadsworth, Marc H., II ^{[4
,6
,7
,8
]}

Hughes, Travis K. ^{[4
,6
,7
,8
]}

Griffin, Gabriel K. ^{[1
,2
,3
,4
,5
,9
]}

Battaglia, Sofia ^{[1
,2
,3
,4
,5
]}

Verga, Julia A. ^{[1
,2
,3
,4
,5
]}

Stephansky, Jason ^{[3
,9
,10
]}

Pastika, Timothy J. ^{[3
,9
,10
]}

Story, Jennifer Lombardi ^{[2
,5
]}

Pinkus, Geraldine S. ^{[9
]}

Pozdnyakova, Olga ^{[9
]}

Galinsky, Ilene ^{[10
]}

Stone, Richard M. ^{[10
]}

Graubert, Timothy A. ^{[2
,5
]}

Shalek, Alex K. ^{[4
,6
,7
,8
]}

Aster, Jon C. ^{[3
,9
]}

Lane, Andrew A. ^{[3
,10
]}

Bernstein, Bradley E. ^{[1
,2
,3
,4
,5
]}

机构：

[1] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

[2] Harvard Med Sch, Boston, MA 02114 USA

[3] Harvard Med Sch, Ludwig Ctr, Boston, MA 02115 USA

[4] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[5] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA

[6] MIT, Dept Chem, Inst Med Engn & Sci, Cambridge, MA 02139 USA

[7] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA

[8] Ragon Inst MGH MIT & Harvard, Cambridge, MA 02139 USA

[9] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA

[10] Dana Farber Canc Inst, Boston, MA 02215 USA

来源：

CELL | 2019年 / 176卷 / 06期

关键词：

STEM-CELLS; SUPPRESSOR-CELLS; LEUKEMIA; PROGENITOR; CANCER; GENOMICS; FUTURE;

D O I：

10.1016/j.cell.2019.01.031

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：

Acute myeloid leukemia (AML) is a heterogeneous disease that resides within a complex microenvironment, complicating efforts to understand how different cell types contribute to disease progression. We combined single-cell RNA sequencing and genotyping to profile 38,410 cells from 40 bone marrow aspirates, including 16 AML patients and five healthy donors. We then applied a machine learning classifier to distinguish a spectrum of malignant cell types whose abundances varied between patients and between subclones in the same tumor. Cell type compositions correlated with prototypic genetic lesions, including an association of FLT3-ITD with abundant progenitor-like cells. Primitive AML cells exhibited dysregulated transcriptional programs with co-expression of stemness and myeloid priming genes and had prognostic significance. Differentiated monocyte-like AML cells expressed diverse immunomodulatory genes and suppressed T cell activity in vitro. In conclusion, we provide single-cell technologies and an atlas of AML cell states, regulators, and markers with implications for precision medicine and immune therapies.

引用

页码：1265 / +

页数：41

共 37 条

[1] Harnessing the immune system in acute myeloid leukaemia [J].

Austin, Rebecca ;

Smyth, Mark J. ;

Lane, Steven W. .

CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY, 2016, 103 :62-77

[2] Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm [J].

Biswas, Subhra K. ;

Mantovani, Alberto .

NATURE IMMUNOLOGY, 2010, 11 (10) :889-896

[3] Mutant NPM1 Maintains the Leukemic State through HOX Expression [J].

Brunetti, Lorenzo ;

Gundry, Michael C. ;

Sorcini, Daniele ;

Guzman, Anna G. ;

Huang, Yung-Hsin ;

Ramabadran, Raghav ;

Gionfriddo, Ilaria ;

Mezzasoma, Federica ;

Milano, Francesca ;

Nabet, Behnam ;

Buckley, Dennis L. ;

Kornblau, Steven M. ;

Lin, Charles Y. ;

Sportoletti, Paolo ;

Martelli, Maria Paola ;

Falini, Brunangelo ;

Goodell, Margaret A. .

CANCER CELL, 2018, 34 (03) :499-+

[4] LILRB4 signalling in leukaemia cells mediates T cell suppression and tumour infiltration [J].

Deng, Mi ;

Gui, Xun ;

Kim, Jaehyup ;

Xie, Li ;

Chen, Weina ;

Li, Zunling ;

He, Licai ;

Chen, Yuanzhi ;

Chen, Heyu ;

Luo, Weiguang ;

Lu, Zhigang ;

Xie, Jingjing ;

Churchill, Hywyn ;

Xu, Yixiang ;

Zhou, Zhan ;

Wu, Guojin ;

Yu, Chenyi ;

John, Samuel ;

Hirayasu, Kouyuki ;

Nam Nguyen ;

Liu, Xiaoye ;

Huang, Fangfang ;

Li, Leike ;

Deng, Hui ;

Tang, Haidong ;

Sadek, Ali H. ;

Zhang, Lingbo ;

Huang, Tao ;

Zou, Yizhou ;

Chen, Benjamin ;

Zhu, Hong ;

Arase, Hisashi ;

Xia, Ningshao ;

Jiang, Youxing ;

Collins, Robert ;

You, M. James ;

Homsi, Jade ;

Unni, Nisha ;

Lewis, Cheryl ;

Chen, Guo-Qiang ;

Fu, Yang-Xin ;

Liao, X. Charlene ;

An, Zhiqiang ;

Zheng, Junke ;

Zhang, Ningyan ;

Zhang, Cheng Cheng .

NATURE, 2018, 562 (7728) :605-+

[5] Developmental and oncogenic programs in H3K27M gliomas dissected by single-cell RNA-seq [J].

Filbin, Mariella G. ;

Tirosh, Itay ;

Hovestadt, Volker ;

Shaw, McKenzie L. ;

Escalante, Leah E. ;

Mathewson, Nathan D. ;

Neftel, Cyril ;

Frank, Nelli ;

Pelton, Kristine ;

Hebert, ChristineM. ;

Haberler, Christine ;

Yizhak, Keren ;

Gojo, Johannes ;

Egervari, Kristof ;

Mount, Christopher ;

van Galen, Peter ;

Bonal, Dennis M. ;

Quang-De Nguyen ;

Beck, Alexander ;

Sinai, Claire ;

Czech, Thomas ;

Dorfer, Christian ;

Goumnerova, Liliana ;

Lavarino, Cinzia ;

Carcaboso, Angel M. ;

Mora, Jaume ;

Mylvaganam, Ravindra ;

Luo, Christina C. ;

Peyrl, Andreas ;

Popovic, Mara ;

Azizi, Amedeo ;

Batchelor, Tracy T. ;

Frosch, Matthew P. ;

Martinez-Lage, Maria ;

Kieran, Mark W. ;

Bandopadhayay, Pratiti ;

Beroukhim, Rameen ;

Fritsch, Gerhard ;

Getz, Gad ;

Rozenblatt-Rosen, Orit ;

Wucherpfennig, Kai W. ;

Louis, David N. ;

Monje, Michelle ;

Slavc, Irene ;

Ligon, Keith L. ;

Golub, Todd R. ;

Regev, Aviv ;

Bernstein, Bradley E. ;

Suva, Mario L. .

SCIENCE, 2018, 360 (6386) :331-335

[6] Seq-Well: portable, low-cost RNA sequencing of single cells at high throughput [J].

Gierahn, Todd M. ;

Wadsworth, Marc H., II ;

Hughes, Travis K. ;

Bryson, Bryan D. ;

Butler, Andrew ;

Satija, Rahul ;

Fortune, Sarah ;

Love, J. Christopher ;

Shalek, Alex K. .

NATURE METHODS, 2017, 14 (04) :395-+

[7] Single-Cell Genomics: A Stepping Stone for Future Immunology Discoveries [J].

Giladi, Amir ;

Amit, Ido .

CELL, 2018, 172 (1-2) :14-21

[8] Single-cell transcriptomics uncovers distinct molecular signatures of stem cells in chronic myeloid leukemia [J].

Giustacchini, Alice ;

Thongjuea, Supat ;

Barkas, Nikolaos ;

Woll, Petter S. ;

Povinelli, Benjamin J. ;

Booth, Christopher A. G. ;

Sopp, Paul ;

Norfo, Ruggiero ;

Rodriguez-Meira, Alba ;

Ashley, Neil ;

Jamieson, Lauren ;

Vyas, Paresh ;

Anderson, Kristina ;

Segerstolpe, Asa ;

Qian, Hong ;

Olsson-Stromberg, Ulla ;

Mustjoki, Satu ;

Sandberg, Rickard ;

Jacobsen, Sten Eirik W. ;

Mead, Adam J. .

NATURE MEDICINE, 2017, 23 (06) :692-+

[9] Coexistence of LMPP-like and GMP-like Leukemia Stem Cells in Acute Myeloid Leukemia [J].

Goardon, Nicolas ;

Marchi, Emanuele ;

Atzberger, Ann ;

Quek, Lynn ;

Schuh, Anna ;

Soneji, Shamit ;

Woll, Petter ;

Mead, Adam ;

Alford, Kate A. ;

Rout, Raj ;

Chaudhury, Salma ;

Gilkes, Amanda ;

Knapper, Steve ;

Beldjord, Kheira ;

Begum, Suriya ;

Rose, Susan ;

Geddes, Nicola ;

Griffiths, Mike ;

Standen, Graham ;

Sternberg, Alexander ;

Cavenagh, Jamie ;

Hunter, Hannah ;

Bowen, David ;

Killick, Sally ;

Robinson, Lisa ;

Price, Andrew ;

Macintyre, Elizabeth ;

Virgo, Paul ;

Burnett, Alan ;

Craddock, Charles ;

Enver, Tariq ;

Jacobsen, Sten Eirik W. ;

Porcher, Catherine ;

Vyas, Paresh .

CANCER CELL, 2011, 19 (01) :138-152

[10] The TRAIL-Induced Cancer Secretome Promotes a Tumor-Supportive Immune Microenvironment via CCR2 [J].

Hartwig, Torsten ;

Montinaro, Antonella ;

von Karstedt, Silvia ;

Sevko, Alexandra ;

Surinova, Silvia ;

Chakravarthy, Ankur ;

Taraborrelli, Lucia ;

Draber, Peter ;

Lafont, Elodie ;

Vargas, Frederick Arce ;

El-Bahrawy, Mona A. ;

Quezada, Sergio A. ;

Walczak, Henning .

MOLECULAR CELL, 2017, 65 (04) :730-+

← 1 2 3 4 →