A cellular hierarchy framework for understanding heterogeneity and predicting drug response in acute myeloid leukemia

被引：176

作者：

Zeng, Andy G. X. ^{[1
,2
]}

Bansal, Suraj ^{[1
]}

Jin, Liqing ^{[1
]}

Mitchell, Amanda ^{[1
]}

Chen, Weihsu Claire ^{[1
,17
]}

Abbas, Hussein A. ^{[3
]}

Chan-Seng-Yue, Michelle ^{[1
]}

Voisin, Veronique ^{[4
]}

van Galen, Peter ^{[5
,6
,7
,8
]}

Tierens, Anne ^{[9
]}

Cheok, Meyling ^{[10
]}

Preudhomme, Claude ^{[10
]}

Dombret, Herve ^{[11
]}

Daver, Naval ^{[3
]}

Futreal, P. Andrew ^{[12
]}

Minden, Mark D. ^{[1
,13
,14
,15
]}

Kennedy, James A. ^{[1
,16
]}

Wang, Jean C. Y. ^{[1
,14
,15
]}

Dick, John E. ^{[1
,2
]}

机构：

[1] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada

[2] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada

[3] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA

[4] Univ Toronto, Donnelly Ctr, Toronto, ON, Canada

[5] Brigham & Womens Hosp, Div Hematol, Boston, MA 02115 USA

[6] Harvard Med Sch, Dept Med, Boston, MA 02115 USA

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

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

[9] Univ Hlth Network, Lab Med Program, Hematopathol, Toronto, ON, Canada

[10] Univ Lille, U1277 CANTHER Canc Heterogene Plast & Resistance, CHU Lille, CNRS,INSERM,UMR9020, Lille, France

[11] Univ Paris Cite, Hop St Louis, AP HP, Dept Hematol, Paris, France

[12] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA

[13] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada

[14] Univ Toronto, Dept Med, Toronto, ON, Canada

[15] Univ Hlth Network, Div Med Oncol & Hematol, Toronto, ON, Canada

[16] Sunnybrook Hlth Sci Ctr, Div Med Oncol & Hematol, Toronto, ON, Canada

[17] Amgen British Columbia, Biol Discovery, Burnaby, BC, Canada

来源：

NATURE MEDICINE | 2022年 / 28卷 / 06期

关键词：

SELF-RENEWAL; STEM-CELLS; CLINICAL-OUTCOMES; AML; SUBCLONES; LANDSCAPE; SIGNATURE; EVOLUTION; THERAPY; CULTURE;

D O I：

10.1038/s41591-022-01819-x

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：

A novel gene expression classifier of AML heterogeneity captures patient-specific variation in leukemia cell composition and predicts clinical responses to treatment. The treatment landscape of acute myeloid leukemia (AML) is evolving, with promising therapies entering clinical translation, yet patient responses remain heterogeneous, and biomarkers for tailoring treatment are lacking. To understand how disease heterogeneity links with therapy response, we determined the leukemia cell hierarchy makeup from bulk transcriptomes of more than 1,000 patients through deconvolution using single-cell reference profiles of leukemia stem, progenitor and mature cell types. Leukemia hierarchy composition was associated with functional, genomic and clinical properties and converged into four overall classes, spanning Primitive, Mature, GMP and Intermediate. Critically, variation in hierarchy composition along the Primitive versus GMP or Primitive versus Mature axes were associated with response to chemotherapy or drug sensitivity profiles of targeted therapies, respectively. A seven-gene biomarker derived from the Primitive versus Mature axis was associated with response to 105 investigational drugs. Cellular hierarchy composition constitutes a novel framework for understanding disease biology and advancing precision medicine in AML.

引用

页码：1212 / +

页数：31

共 69 条

[1] Single cell T cell landscape and T cell receptor repertoire profiling of AML in context of PD-1 blockade therapy [J].

Abbas, Hussein A. ;

Hao, Dapeng ;

Tomczak, Katarzyna ;

Barrodia, Praveen ;

Im, Jin Seon ;

Reville, Patrick K. ;

Alaniz, Zoe ;

Wang, Wei ;

Wang, Ruiping ;

Wang, Feng ;

Al-Atrash, Gheath ;

Takahashi, Koichi ;

Ning, Jing ;

Ding, Maomao ;

Beird, Hannah C. ;

Mathews, Jairo T. ;

Little, Latasha ;

Zhang, Jianhua ;

Basu, Sreyashi ;

Konopleva, Marina ;

Marques-Piubelli, Mario L. ;

Solis, Luisa M. ;

Parra, Edwin Roger ;

Lu, Wei ;

Tamegnon, Auriole ;

Garcia-Manero, Guillermo ;

Green, Michael R. ;

Sharma, Padmanee ;

Allison, James P. ;

Kornblau, Steven M. ;

Rai, Kunal ;

Wang, Linghua ;

Daver, Naval ;

Futreal, Andrew .

NATURE COMMUNICATIONS, 2021, 12 (01)

[2]

Aibar S, 2017, NAT METHODS, V14, P1083, DOI [10.1038/NMETH.4463, 10.1038/nmeth.4463]

[3] The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions (vol 24, pg 103, 2017) [J].

Bolouri, Hamid ;

Farrar, Jason E. ;

Triche, Timothy, Jr. ;

Ries, Rhonda E. ;

Lim, Emilia L. ;

Alonzo, Todd A. ;

Ma, Yussanne ;

Moore, Richard ;

Mungall, Andrew J. ;

Marra, Marco A. ;

Zhang, Jinghui ;

Ma, Xiaotu ;

Liu, Yu ;

Liu, Yanling ;

Auvil, Jaime M. Guidry ;

Davidsen, Tanja M. ;

Gesuwan, Patee ;

Hermida, Leandro C. ;

Salhia, Bodour ;

Capone, Stephen ;

Ramsingh, Giridharan ;

Zwaan, Christian Michel ;

Noort, Sanne ;

Piccolo, Stephen R. ;

Kolb, E. Anders ;

Gamis, Alan S. ;

Smith, Malcolm A. ;

Gerhard, Daniela S. ;

Meshinchi, Soheil .

NATURE MEDICINE, 2018, 24 (01) :103-+

[4] Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell [J].

Bonnet, D ;

Dick, JE .

NATURE MEDICINE, 1997, 3 (07) :730-737

[5] 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-+

[6]

BUICK RN, 1979, BLOOD, V54, P95

[7] Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study [J].

Castaigne, Sylvie ;

Pautas, Cecile ;

Terre, Christine ;

Raffoux, Emmanuel ;

Bordessoule, Dominique ;

Bastie, Jean-Noel ;

Legrand, Ollivier ;

Thomas, Xavier ;

Turlure, Pascal ;

Reman, Oumedaly ;

de Revel, Thierry ;

Gastaud, Lauris ;

de Gunzburg, Noemie ;

Contentin, Nathalie ;

Henry, Estelle ;

Marolleau, Jean-Pierre ;

Aljijakli, Ahmad ;

Rousselot, Philippe ;

Fenaux, Pierre ;

Preudhomme, Claude ;

Chevret, Sylvie ;

Dombret, Herve .

LANCET, 2012, 379 (9825) :1508-1516

[8] THE CELLULAR BASIS OF SELF RENEWAL IN CULTURE BY HUMAN ACUTE MYELOBLASTIC-LEUKEMIA BLAST CELL PROGENITORS [J].

CHANG, LJA ;

TILL, JE ;

MCCULLOCH, EA .

JOURNAL OF CELLULAR PHYSIOLOGY, 1980, 102 (02) :217-222

[9] An Integrated Analysis of Heterogeneous Drug Responses in Acute Myeloid Leukemia That Enables the Discovery of Predictive Biomarkers [J].

Chen, Weihsu C. ;

Yuan, Julie S. ;

Xing, Yan ;

Mitchell, Amanda ;

Mbong, Nathan ;

Popescu, Andreea C. ;

McLeod, Jessica ;

Gerhard, Gitte ;

Kennedy, James A. ;

Bogdanoski, Goce ;

Lauriault, Stevan ;

Perdu, Sofie ;

Merkulova, Yulia ;

Minden, Mark D. ;

Hogge, Donna E. ;

Guidos, Cynthia ;

Dick, John E. ;

Wang, Jean C. Y. .

CANCER RESEARCH, 2016, 76 (05) :1214-1224

[10] Immune Escape of Relapsed AML Cells after Allogeneic Transplantation [J].

Christopher, M. J. ;

Petti, A. A. ;

Rettig, M. P. ;

Miller, C. A. ;

Chendamarai, E. ;

Duncavage, E. J. ;

Klco, J. M. ;

Helton, N. M. ;

O'Laughlin, M. ;

Fronick, C. C. ;

Fulton, R. S. ;

Wilson, R. K. ;

Wartman, L. D. ;

Welch, J. S. ;

Heath, S. E. ;

Baty, J. D. ;

Payton, J. E. ;

Graubert, T. A. ;

Link, D. C. ;

Walter, M. J. ;

Westervelt, P. ;

Ley, T. J. ;

DiPersio, J. F. .

NEW ENGLAND JOURNAL OF MEDICINE, 2018, 379 (24) :2330-2341

← 1 2 3 4 5 6 7 →