TBL1XR1 Mutations Drive Extranodal Lymphoma by Inducing a Pro-tumorigenic Memory Fate.
The most aggressive B cell lymphomas frequently manifest extranodal distribution and carry somatic mutations in the poorly characterized gene TBL1XR1. Here, we show that TBL1XR1 mutations skew the humoral immune response toward generating abnormal immature memory B cells (MB), while impairing plasma cell differentiation. At the molecular level, TBL1XR1 mutants co-opt SMRT/HDAC3 repressor complexes toward binding the MB cell transcription factor (TF) BACH2 at the expense of the germinal center (GC) TF BCL6, leading to pre-memory transcriptional reprogramming and cell-fate bias. Upon antigen recall, TBL1XR1 mutant MB cells fail to differentiate into plasma cells and instead preferentially reenter new GC reactions, providing evidence for a cyclic reentry lymphomagenesis mechanism. Ultimately, TBL1XR1 alterations lead to a striking extranodal immunoblastic lymphoma phenotype that mimics the human disease. Both human and murine lymphomas feature expanded MB-like cell populations, consistent with a MB-cell origin and delineating an unforeseen pathway for malignant transformation of the immune system.
Pubmed ID: 32619424 RIS Download
Research resources used in this publication
-
B6.129P2-Ptprca Igh
- 129S4/SvJaeSor-Gt(ROSA)26Sortm1(FLP1)Dym/J (RRID:IMSR_JAX:003946) (organism)
- B6.Cg-Tg(TcraTcrb)425Cbn/J (RRID:IMSR_JAX:004194) (organism)
- B6.129X1-Gt(ROSA)26Sortm1(EYFP)Cos/J (RRID:IMSR_JAX:006148) (organism)
-
B6.SJL-Ptprca Pepc
- B6.129S2-Ighmtm1Cgn/J (RRID:IMSR_JAX:002288) (organism)
- B6.129P2(C)-Cd19tm1(cre)Cgn/J (RRID:IMSR_JAX:006785) (organism)
- B6.129P2(Cg)-Ighg1tm1(cre)Cgn/J (RRID:IMSR_JAX:010611) (organism)
- C57BL/6J (RRID:IMSR_JAX:000664) (organism)
- pCMV-VSV-G (RRID:Addgene_8454) (plasmid)
- pLIX_403 (RRID:Addgene_41395) (plasmid)
- pCMV(CAT)T7-SB100 (RRID:Addgene_34879) (plasmid)
- pSBtet-GP (RRID:Addgene_60495) (plasmid)
- OCI-Ly1 (RRID:CVCL_1879) (cell line)
- HEK293T (RRID:CVCL_0063) (cell line)
- U-2932 (RRID:CVCL_1896) (cell line)
Additional research tools detected in this publication
Antibodies used in this publication
- Anti-Human CD27-167Er (RRID:AB_2811093)
- Anti-Human CD10 (HI10a)-156Gd (RRID:AB_2802107)
- Peroxidase AffiniPure Goat Anti-Mouse IgG, light chain specific (RRID:AB_2338512)
- Peroxidase IgG Fraction Monoclonal Mouse Anti-Rabbit IgG, light chain specific (RRID:AB_2339149)
- Biotin-SP-AffiniPure Goat Anti-Rat IgG (H+L) (min X Hu,Bov,Hrs,Ms,Rb Sr Prot) (RRID:AB_2338179)
- Mouse Anti-Human TBL1XR1 Monoclonal Antibody, Unconjugated, Clone 3G7 (RRID:AB_490081)
- Rabbit Anti-Human BACH2 Polyclonal Antibody, Unconjugated (RRID:AB_2045059)
- Rabbit Anti-SMRTe Polyclonal antibody, Unconjugated (RRID:AB_310286)
- β-Actin Antibody (C4) (RRID:AB_2714189)
- HDAC3 Antibody (RRID:AB_2715509)
- HDAC3 (H-99) (RRID:AB_2118706)
- Bcl-6 (D-8) (RRID:AB_2063455)
- Bcl-6 (N-3) (RRID:AB_2063450)
- Ki-67 (D3B5) Rabbit mAb (Mouse Preferred; IHC Formulated) (RRID:AB_2620142)
- CD3 antibody [SP7] (RRID:AB_443425)
- Rabbit Anti-Mouse IgG H&L (RRID:AB_2614925)
- InVivoPlus mouse IgG2a isotype control (RRID:AB_1107771)
- InVivoMab anti-mouse IL-9 (RRID:AB_10950648)
- InVivoPlus polyclonal Armenian hamster IgG (RRID:AB_1107773)
- InVivoPlus anti-mouse CD154 (CD40L) (RRID:AB_1107601)
- NCoR2 Polyclonal Antibody (RRID:AB_2149135)
- CD38 Monoclonal Antibody (38C03 (SPC32)) (RRID:AB_10986743)
- AID Monoclonal Antibody (1AID-2E11) (RRID:AB_2633326)
- Goat Anti-Mouse IgG (H+L) Antibody, Alexa Fluor ?? 647 Conjugated (RRID:AB_2535804)
- Goat anti-Chicken IgY (H+L) Secondary Antibody, HRP (RRID:AB_2534727)
- Goat Anti-Mouse Ephrin-b1 Polyclonal antibody, Biotin Conjugated (RRID:AB_2293418)
- Mouse EDG-1/S1P1 MAb (Clone 713412) (RRID:AB_10994183)
- IL-9 Monoclonal Antibody (RM9A4), eFluor™ 660, eBioscience (RRID:AB_11218680)
- Brilliant Violet 421(TM) anti-mouse CD138 (Syndecan-1) (RRID:AB_11203544)
- PE/Cyanine7 anti-mouse CD138 (Syndecan-1) (RRID:AB_2562198)
- PerCP/Cyanine5.5 anti-mouse CD95 (Fas) (RRID:AB_2632905)
- PerCP/Cyanine5.5 anti-MU/HU GL7 Antigen (T/B Cell Act. Marker) (RRID:AB_2562979)
- APC/Cyanine7 anti-mouse CD38 (RRID:AB_2616968)
- PE anti-mouse/human CD45R/B220 (RRID:AB_312993)
- APC/Cyanine7 anti-mouse/human CD45R/B220 (RRID:AB_313007)
- Brilliant Violet 421(TM) anti-mouse/human CD45R/B220 (RRID:AB_11203896)
- Alexa Fluor(R) 647 anti-mouse Blimp-1 (RRID:AB_2565618)
- PE anti-mouse/human Bcl-6 (RRID:AB_2561375)
- APC anti-mouse CD3 (RRID:AB_2561455)
- Brilliant Violet 421(TM) anti-mouse CD80 (RRID:AB_10900989)
- PerCP/Cyanine5.5 anti-mouse CD45.2 (RRID:AB_893350)
- APC/Cyanine7 anti-mouse CD4 (RRID:AB_312699)
- PE anti-human/mouse/rat PCNA (RRID:AB_314698)
- Brilliant Violet 510(TM) anti-mouse CD62L (RRID:AB_2561537)
- Human TruStain FcX™ (Fc Receptor Blocking Solution) (RRID:AB_2818986)
- CD 45R (b220) (RRID:AB_393581)
- CD138 (RRID:AB_394998)
- T- and B-Cell Activation Antigen (RRID:AB_10716056)
- Rat Anti-T-, B-Cell Activation Antigen Monoclonal Antibody, FITC Conjugated, Clone GL7 (RRID:AB_394981)
- CD25 (RRID:AB_10893596)
- Rat Anti-CD19 Monoclonal Antibody, FITC Conjugated, Clone 1D3 (RRID:AB_395049)
- CD117 (RRID:AB_10563203)
- CD196 (CCR6) (RRID:AB_2738926)
- IgM (RRID:AB_2741428)
- Rat Anti-IgM Monoclonal Antibody, FITC Conjugated, Clone II/41 (RRID:AB_394857)
- CD138 (Syndecan-1) (RRID:AB_2738805)
- IgG1 (RRID:AB_2737664)
- IgG1 (RRID:AB_393553)
- BV510 Rat Anti-Mouse IgD (RRID:AB_2737003)
- IgD (RRID:AB_2742121)
- CXCR5 (RRID:AB_394301)
- CD184 (RRID:AB_394307)
- CD86 (B7-2) (RRID:AB_2738663)
- Rat Anti-Mouse CD86 Monoclonal Antibody, PE-Cy7 Conjugated, Clone GL1 (RRID:AB_1727518)
- CD38 (RRID:AB_2739992)
- PE-Cy™7 Hamster Anti-Mouse CD95 (RRID:AB_396768)
- CD45R (B220) (RRID:AB_2738472)
- Rat Anti-CD45R / B220 Monoclonal Antibody, PE-Cy7 Conjugated, Clone RA3-6B2 (RRID:AB_394458)
- CD45R/B220 (RRID:AB_394617)
- Rat Anti-Mouse CD44 Monoclonal Antibody, PE-Cy7 Conjugated, Clone IM7 (RRID:AB_1727484)
- Rat Anti-CD16 / CD32 Monoclonal Antibody, Unconjugated, Clone 2.4G2 (RRID:AB_394657)
- CD279 (PD-1) Monoclonal Antibody (J43), FITC, eBioscience (RRID:AB_465473)
- CD45.1 Monoclonal Antibody (A20), PerCP-Cyanine5.5, eBioscience (RRID:AB_1107003)
- CD184 (CXCR4) Monoclonal Antibody (2B11), PE, eBioscience (RRID:AB_891393)
- CD38 Monoclonal Antibody (90), APC, eBioscience (RRID:AB_469381)
Associated grants
- Agency: NCI NIH HHS, United States
Id: P30 CA008748 - Agency: NCI NIH HHS, United States
Id: P30 CA016672 - Agency: NCI NIH HHS, United States
Id: R35 CA220499
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Bio X Cell (tool)
RRID:SCR_004997
Commercial supplier and developer of in vivo antibodies. Provides antibodies and antibody production services.
View all literature mentionsBiopython (tool)
RRID:SCR_007173
Biopython is a set of freely available tools for biological computation written in Python by an international team of developers. It is a distributed collaborative effort to develop Python libraries and applications which address the needs of current and future work in bioinformatics. The source code is made available under the Biopython License, which is extremely liberal and compatible with almost every license in the world. It works along with the Open Bioinformatics Foundation, who generously host it''s website, bug tracker, and mailing lists. Sponsor: This resource is supported by the Open Bioinformatics Foundation. Keywords: Tool, Software, Python, Biological, Computation, Bioinformatics,
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Software that enables rapid tool creation by providing a robust, pluggable development framework that simplifies and unifies data file access, and performs standard proteomics and LCMS dataset computations.
View all literature mentionsMass spectrometry Interactive Virtual Environment (MassIVE) (tool)
RRID:SCR_013665
Mass spectrometry Interactive Virtual Environment (MassIVE) is a community resource developed by the NIH-funded Center for Computational Mass Spectrometry to promote the global, free exchange of mass spectrometry data. Data repository for proteomics data.
View all literature mentionsAnti-Human CD27-167Er (antibody)
RRID:AB_2811093
This monoclonal targets CD27
View all literature mentionsAnti-Human CD10 (HI10a)-156Gd (antibody)
RRID:AB_2802107
This monoclonal targets CD10
View all literature mentionsPeroxidase AffiniPure Goat Anti-Mouse IgG, light chain specific (antibody)
RRID:AB_2338512
This polyclonal secondary targets IgG, Light Chain Specific
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RRID:AB_2339149
This monoclonal secondary targets IgG, Light Chain Specific
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RRID:AB_2338179
This unknown targets Rat IgG (H+L)
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RRID:AB_490081
This monoclonal targets Human TBL1XR1
View all literature mentionsRabbit Anti-Human BACH2 Polyclonal Antibody, Unconjugated (antibody)
RRID:AB_2045059
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This polyclonal targets SMRTe
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This monoclonal targets HDAC3
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RRID:AB_2063450
This polyclonal targets Bcl-6 (N-3)
View all literature mentionsKi-67 (D3B5) Rabbit mAb (Mouse Preferred; IHC Formulated) (antibody)
RRID:AB_2620142
This monoclonal targets Ki-67
View all literature mentionsCD3 antibody [SP7] (antibody)
RRID:AB_443425
This monoclonal targets CD3 antibody [SP7]
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RRID:AB_2614925
This polyclonal secondary targets IgG H&L
View all literature mentionsInVivoPlus mouse IgG2a isotype control (antibody)
RRID:AB_1107771
This isotype control targets Unknown Specificity
View all literature mentionsInVivoMab anti-mouse IL-9 (antibody)
RRID:AB_10950648
This monoclonal targets IL-9
View all literature mentionsInVivoPlus polyclonal Armenian hamster IgG (antibody)
RRID:AB_1107773
This isotype control targets Unknown Specificity
View all literature mentionsInVivoPlus anti-mouse CD154 (CD40L) (antibody)
RRID:AB_1107601
This monoclonal targets CD40L (CD154)
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RRID:AB_2149135
This unknown targets NCoR2
View all literature mentionsCD38 Monoclonal Antibody (38C03 (SPC32)) (antibody)
RRID:AB_10986743
This monoclonal targets CD38
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RRID:AB_2633326
This monoclonal targets AID
View all literature mentionsGoat Anti-Mouse IgG (H+L) Antibody, Alexa Fluor ?? 647 Conjugated (antibody)
RRID:AB_2535804
This unknown targets IgG (H+L)
View all literature mentionsGoat anti-Chicken IgY (H+L) Secondary Antibody, HRP (antibody)
RRID:AB_2534727
This polyclonal secondary targets IgY (H+L)
View all literature mentionsGoat Anti-Mouse Ephrin-b1 Polyclonal antibody, Biotin Conjugated (antibody)
RRID:AB_2293418
This polyclonal targets Mouse Ephrin-B1
View all literature mentionsMouse EDG-1/S1P1 MAb (Clone 713412) (antibody)
RRID:AB_10994183
This monoclonal targets Mouse EDG-1/S1P1 MAb (Clone 713412)
View all literature mentionsIL-9 Monoclonal Antibody (RM9A4), eFluor™ 660, eBioscience (antibody)
RRID:AB_11218680
This monoclonal targets IL-9
View all literature mentionsBrilliant Violet 421(TM) anti-mouse CD138 (Syndecan-1) (antibody)
RRID:AB_11203544
This monoclonal targets CD138
View all literature mentionsPE/Cyanine7 anti-mouse CD138 (Syndecan-1) (antibody)
RRID:AB_2562198
This monoclonal targets CD138
View all literature mentionsPerCP/Cyanine5.5 anti-mouse CD95 (Fas) (antibody)
RRID:AB_2632905
This monoclonal targets CD95
View all literature mentionsPerCP/Cyanine5.5 anti-MU/HU GL7 Antigen (T/B Cell Act. Marker) (antibody)
RRID:AB_2562979
This monoclonal targets GL7
View all literature mentionsAPC/Cyanine7 anti-mouse CD38 (antibody)
RRID:AB_2616968
This monoclonal targets CD38
View all literature mentionsPE anti-mouse/human CD45R/B220 (antibody)
RRID:AB_312993
This monoclonal targets CD45R
View all literature mentionsAPC/Cyanine7 anti-mouse/human CD45R/B220 (antibody)
RRID:AB_313007
This monoclonal targets CD45R
View all literature mentionsBrilliant Violet 421(TM) anti-mouse/human CD45R/B220 (antibody)
RRID:AB_11203896
This monoclonal targets CD45R
View all literature mentionsAlexa Fluor(R) 647 anti-mouse Blimp-1 (antibody)
RRID:AB_2565618
This monoclonal targets Blimp-1
View all literature mentionsPE anti-mouse/human Bcl-6 (antibody)
RRID:AB_2561375
This monoclonal targets Bcl-6
View all literature mentionsAPC anti-mouse CD3 (antibody)
RRID:AB_2561455
This monoclonal targets CD3
View all literature mentionsBrilliant Violet 421(TM) anti-mouse CD80 (antibody)
RRID:AB_10900989
This monoclonal targets CD80
View all literature mentionsPerCP/Cyanine5.5 anti-mouse CD45.2 (antibody)
RRID:AB_893350
This monoclonal targets CD45.2
View all literature mentionsAPC/Cyanine7 anti-mouse CD4 (antibody)
RRID:AB_312699
This monoclonal targets CD4
View all literature mentionsPE anti-human/mouse/rat PCNA (antibody)
RRID:AB_314698
This monoclonal targets PCNA
View all literature mentionsBrilliant Violet 510(TM) anti-mouse CD62L (antibody)
RRID:AB_2561537
This monoclonal targets CD62L
View all literature mentionsHuman TruStain FcX™ (Fc Receptor Blocking Solution) (antibody)
RRID:AB_2818986
This unknown targets FC receptors
View all literature mentionsCD 45R (b220) (antibody)
RRID:AB_393581
This monoclonal targets A suspension of Abelson murine leukemia virus-induced pre-B tumor cells.
View all literature mentionsCD138 (antibody)
RRID:AB_394998
This monoclonal targets CD138 (Syndecan-1)
View all literature mentionsT- and B-Cell Activation Antigen (antibody)
RRID:AB_10716056
This monoclonal targets T- and B-Cell Activation Antigen
View all literature mentionsRat Anti-T-, B-Cell Activation Antigen Monoclonal Antibody, FITC Conjugated, Clone GL7 (antibody)
RRID:AB_394981
This monoclonal targets T-, B-Cell Activation Antigen
View all literature mentionsCD25 (antibody)
RRID:AB_10893596
This monoclonal targets CD25 (IL-2 Receptor α)
View all literature mentionsRat Anti-CD19 Monoclonal Antibody, FITC Conjugated, Clone 1D3 (antibody)
RRID:AB_395049
This monoclonal targets CD19
View all literature mentionsCD196 (CCR6) (antibody)
RRID:AB_2738926
This monoclonal targets CD196 (CCR6)
View all literature mentionsRat Anti-IgM Monoclonal Antibody, FITC Conjugated, Clone II/41 (antibody)
RRID:AB_394857
This monoclonal targets IgM
View all literature mentionsCD138 (Syndecan-1) (antibody)
RRID:AB_2738805
This monoclonal targets CD138 (Syndecan-1)
View all literature mentionsBV510 Rat Anti-Mouse IgD (antibody)
RRID:AB_2737003
This monoclonal targets IgD
View all literature mentionsCD86 (B7-2) (antibody)
RRID:AB_2738663
This monoclonal targets CD86 (B7-2)
View all literature mentionsRat Anti-Mouse CD86 Monoclonal Antibody, PE-Cy7 Conjugated, Clone GL1 (antibody)
RRID:AB_1727518
This monoclonal targets Mouse CD86
View all literature mentionsPE-Cy™7 Hamster Anti-Mouse CD95 (antibody)
RRID:AB_396768
This monoclonal targets CD95
View all literature mentionsCD45R (B220) (antibody)
RRID:AB_2738472
This monoclonal targets CD45R (B220)
View all literature mentionsRat Anti-CD45R / B220 Monoclonal Antibody, PE-Cy7 Conjugated, Clone RA3-6B2 (antibody)
RRID:AB_394458
This monoclonal targets CD45R (B220)
View all literature mentionsCD45R/B220 (antibody)
RRID:AB_394617
This monoclonal targets CD45R (B220)
View all literature mentionsRat Anti-Mouse CD44 Monoclonal Antibody, PE-Cy7 Conjugated, Clone IM7 (antibody)
RRID:AB_1727484
This monoclonal targets Mouse CD44
View all literature mentionsRat Anti-CD16 / CD32 Monoclonal Antibody, Unconjugated, Clone 2.4G2 (antibody)
RRID:AB_394657
This monoclonal targets CD16 / CD32
View all literature mentionsCD279 (PD-1) Monoclonal Antibody (J43), FITC, eBioscience (antibody)
RRID:AB_465473
This monoclonal targets CD279 (PD-1)
View all literature mentionsCD45.1 Monoclonal Antibody (A20), PerCP-Cyanine5.5, eBioscience (antibody)
RRID:AB_1107003
This monoclonal targets CD45.1
View all literature mentionsCD184 (CXCR4) Monoclonal Antibody (2B11), PE, eBioscience (antibody)
RRID:AB_891393
This monoclonal targets CD184 (CXCR4)
View all literature mentionsCD38 Monoclonal Antibody (90), APC, eBioscience (antibody)
RRID:AB_469381
This monoclonal targets CD38
View all literature mentions
B6.129P2-Ptprca Igh/J (organism)
RRID:IMSR_JAX:007594
Mus musculus with name B6.129P2-Ptprca Igh
129S4/SvJaeSor-Gt(ROSA)26Sortm1(FLP1)Dym/J (organism)
RRID:IMSR_JAX:003946
Mus musculus with name 129S4/SvJaeSor-Gt(ROSA)26Sortm1(FLP1)Dym/J from IMSR.
View all literature mentionsB6.Cg-Tg(TcraTcrb)425Cbn/J (organism)
RRID:IMSR_JAX:004194
Mus musculus with name B6.Cg-Tg(TcraTcrb)425Cbn/J from IMSR.
View all literature mentionsB6.129X1-Gt(ROSA)26Sortm1(EYFP)Cos/J (organism)
RRID:IMSR_JAX:006148
Mus musculus with name B6.129X1-Gt(ROSA)26Sortm1(EYFP)Cos/J from IMSR.
View all literature mentions
B6.SJL-Ptprca Pepc/BoyJ (organism)
RRID:IMSR_JAX:002014
Mus musculus with name B6.SJL-Ptprca Pepc
B6.129S2-Ighmtm1Cgn/J (organism)
RRID:IMSR_JAX:002288
Mus musculus with name B6.129S2-Ighmtm1Cgn/J from IMSR.
View all literature mentionsB6.129P2(C)-Cd19tm1(cre)Cgn/J (organism)
RRID:IMSR_JAX:006785
Mus musculus with name B6.129P2(C)-Cd19tm1(cre)Cgn/J from IMSR.
View all literature mentionsB6.129P2(Cg)-Ighg1tm1(cre)Cgn/J (organism)
RRID:IMSR_JAX:010611
Mus musculus with name B6.129P2(Cg)-Ighg1tm1(cre)Cgn/J from IMSR.
View all literature mentionsC57BL/6J (organism)
RRID:IMSR_JAX:000664
Mus musculus with name C57BL/6J from IMSR.
View all literature mentionsOCI-Ly1 (cell line)
RRID:CVCL_1879
Cell line OCI-Ly1 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsHEK293T (cell line)
RRID:CVCL_0063
Cell line HEK293T is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentionsU-2932 (cell line)
RRID:CVCL_1896
Cell line U-2932 is a Cancer cell line with a species of origin Homo sapiens
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