BTG1 mutation yields supercompetitive B cells primed for malignant transformation

被引：18

作者：

Mlynarczyk, Coraline ^{[1
,2
]}

Teater, Matt ^{[1
,2
]}

Pae, Juhee ^{[3
]}

Chin, Christopher R. ^{[1
,2
,4
,5
,6
]}

Wang, Ling ^{[1
,2
]}

Arulraj, Theinmozhi ^{[7
,8
]}

Barisic, Darko ^{[1
,2
]}

Papin, Antonin ^{[9
]}

Hoehn, Kenneth B. ^{[10
]}

Kots, Ekaterina ^{[4
]}

Ersching, Jonatan ^{[3
,22
]}

Bandyopadhyay, Arnab ^{[7
,8
]}

Barin, Ersilia ^{[2
,11
]}

Poh, Hui Xian ^{[2
,11
]}

Evans, Chiara M. ^{[11
,12
,13
,14
]}

Chadburn, Amy ^{[9
]}

Chen, Zhengming ^{[15
]}

Shen, Hao ^{[1
,2
]}

Isles, Hannah M. ^{[1
,2
]}

Pelzer, Benedikt ^{[1
,2
]}

Tsialta, Ioanna ^{[1
,2
]}

Doane, Ashley S. ^{[1
,2
,6
]}

Geng, Huimin ^{[16
]}

Rehman, Muhammad Hassan ^{[1
,2
,17
]}

Melnick, Jonah ^{[1
,2
]}

Morgan, Wyatt ^{[1
,2
]}

Nguyen, Diu T. T. ^{[12
,13
,14
,18
]}

Elemento, Olivier ^{[4
,19
]}

Kharas, Michael G. ^{[12
,13
,14
]}

Jaffrey, Samie R. ^{[2
,11
]}

Scott, David W. ^{[20
]}

Khelashvili, George ^{[4
,6
]}

Meyer-Hermann, Michael ^{[7
,8
,21
]}

Victora, Gabriel D. ^{[3
]}

Melnick, Ari ^{[1
,2
]}

机构：

[1] Weill Cornell Med, Div Hematol & Oncol, Dept Med, New York, NY 10021 USA

[2] Weill Cornell Med, Meyer Canc Ctr, New York, NY 10021 USA

[3] Rockefeller Univ, Lab Lymphocyte Dynam, 1230 York Ave, New York, NY 10021 USA

[4] Weill Cornell Med, Dept Physiol & Biophys, New York, NY USA

[5] Triinst PhD Program Computat Biomed, New York, NY USA

[6] Weill Cornell Med, Inst Computat Biomed, New York, NY USA

[7] Helmholtz Ctr Infect Res, Dept Syst Immunol, Braunschweig, Germany

[8] Helmholtz Ctr Infect Res, Braunschweig Integrated Ctr Syst Biol BRICS, Braunschweig, Germany

[9] Weill Cornell Med, Dept Pathol & Lab Med, New York, NY USA

[10] Yale Sch Med, Dept Pathol, New Haven, CT USA

[11] Weill Cornell Med, Dept Pharmacol, New York, NY USA

[12] Mem Sloan Kettering Canc Ctr, Mol Pharmacol Program, 1275 York Ave, New York, NY 10021 USA

[13] Mem Sloan Kettering Canc Ctr, Ctr Cell Engn, Ctr Stem Cell Biol, Ctr Expt Therapeut, 1275 York Ave, New York, NY 10021 USA

[14] Mem Sloan Kettering Canc Ctr, Ctr Hematol Malignancies, 1275 York Ave, New York, NY 10021 USA

[15] Weill Cornell Med, Div Biostat, Dept Populat Hlth Sci, New York, NY USA

[16] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA USA

[17] Weill Cornell Med Qatar, Doha, Qatar

[18] Queen Mary Univ London, Ctr Haemato Oncol, Barts Canc Inst, London, England

[19] Weill Cornell Med, Caryl & Israel Englander Inst Precis Med, New York, NY USA

[20] BC Canc, Ctr Lymphoid Canc, Vancouver, BC, Canada

[21] Tech Univ Carolo Wilhelmina Braunschweig, Inst Biochem Biotechnol & Bioinformat, Braunschweig, Germany

[22] Gordian Biotechnol, San Francisco, CA USA

来源：

SCIENCE | 2023年 / 379卷 / 6629期

基金：

瑞士国家科学基金会;

关键词：

DIFFERENTIAL EXPRESSION ANALYSIS; GERMINAL CENTER; DYNAMIC REGULATION; CLONAL SELECTION; C-MYC; PROTEIN; IMMUNOGLOBULIN; LYMPHOMA; GENES; SIGNATURES;

D O I：

10.1126/science.abj7412

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Multicellular life requires altruistic cooperation between cells. The adaptive immune system is a notable exception, wherein germinal center B cells compete vigorously for limiting positive selection signals. Studying primary human lymphomas and developing new mouse models, we found that mutations affecting BTG1 disrupt a critical immune gatekeeper mechanism that strictly limits B cell fitness during antibody affinity maturation. This mechanism converted germinal center B cells into supercompetitors that rapidly outstrip their normal counterparts. This effect was conferred by a small shift in MYC protein induction kinetics but resulted in aggressive invasive lymphomas, which in humans are linked to dire clinical outcomes. Our findings reveal a delicate evolutionary trade-off between natural selection of B cells to provide immunity and potentially dangerous features that recall the more competitive nature of unicellular organisms.

引用

页码：252 / +

页数：24

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