Developmental partitioning of SYK and ZAP70 prevents autoimmunity and cancer.
Even though SYK and ZAP70 kinases share high sequence homology and serve analogous functions, their expression in B and T cells is strictly segregated throughout evolution. Here, we identified aberrant ZAP70 expression as a common feature in a broad range of B cell malignancies. We validated SYK as the kinase that sets the thresholds for negative selection of autoreactive and premalignant clones. When aberrantly expressed in B cells, ZAP70 competes with SYK at the BCR signalosome and redirects SYK from negative selection to tonic PI3K signaling, thereby promoting B cell survival. In genetic mouse models for B-ALL and B-CLL, conditional expression of Zap70 accelerated disease onset, while genetic deletion impaired malignant transformation. Inducible activation of Zap70 during B cell development compromised negative selection of autoreactive B cells, resulting in pervasive autoantibody production. Strict segregation of the two kinases is critical for normal B cell selection and represents a central safeguard against the development of autoimmune disease and B cell malignancies.
Pubmed ID: 33878293 RIS Download
Research resources used in this publication
- U266B1 (RRID:CVCL_0566) (cell line)
- LP-1 (RRID:CVCL_0012) (cell line)
- JJN-3 (RRID:CVCL_2078) (cell line)
- L-428 (RRID:CVCL_1361) (cell line)
- L-1236 (RRID:CVCL_2096) (cell line)
- SU-DHL-4 (RRID:CVCL_0539) (cell line)
- SU-DHL-2 (RRID:CVCL_9550) (cell line)
- OCI-Ly7 (RRID:CVCL_1881) (cell line)
- OCI-Ly3 (RRID:CVCL_8800) (cell line)
- Toledo (RRID:CVCL_3611) (cell line)
- Daudi (RRID:CVCL_0008) (cell line)
- Ramos (RRID:CVCL_0597) (cell line)
- Raji (RRID:CVCL_0511) (cell line)
- Z-138 (RRID:CVCL_B077) (cell line)
- Mino (RRID:CVCL_1872) (cell line)
- JURL-MK2 (RRID:CVCL_2087) (cell line)
- Kasumi-2 (RRID:CVCL_0590) (cell line)
- RCH-ACV (RRID:CVCL_1851) (cell line)
- 697 (RRID:CVCL_0079) (cell line)
- TOM-1 (RRID:CVCL_1895) (cell line)
- SUP-B15 (RRID:CVCL_0103) (cell line)
- Reh (RRID:CVCL_1650) (cell line)
- RS4;11 (RRID:CVCL_0093) (cell line)
- SEM (RRID:CVCL_0095) (cell line)
- KOPN-8 (RRID:CVCL_1866) (cell line)
-
NOD.Cg-KitW-41J Tyr<+ Prkdc
- B6.C(Cg)-Cd79atm1(cre)Reth/EhobJ (RRID:IMSR_JAX:020505) (organism)
Additional research tools detected in this publication
Antibodies used in this publication
- AffiniPure F(ab')2 Fragment Goat Anti-Human IgM, Fc5µ Fragment Specific (min X Bov Sr Prot) (RRID:AB_2337553)
- Zap-70 (D1C10E) XP(tm) Rabbit mAb (RRID:AB_2218656)
- TBP Antibody (RRID:AB_10949159)
- Syk (4D10) Mouse mAb (RRID:AB_2799953)
- Syk (D3Z1E) XP Rabbit Antibody (RRID:AB_2687924)
- Phospho-Zap-70 (Tyr319)/Syk (Tyr352) (65E4) Rabbit mAb (RRID:AB_2218658)
- PLCgamma1 (D9H10) XP Rabbit mAb (RRID:AB_10691383)
- Phospho-PLCgamma1 (Tyr783) Antibody (RRID:AB_330855)
- PLCγ2 Antibody (RRID:AB_2299586)
- Phospho-PLC-gamma-2 (Tyr1217) Antibody (RRID:AB_2299548)
- NFAT2 (D15F1) Rabbit mAb (RRID:AB_10829466)
- NFAT1 (D43B1) XP Rabbit mAb (RRID:AB_10834808)
- Histone H3 (D1H2) XP Rabbit mAb (RRID:AB_10544537)
- FoxO1 (C29H4) Rabbit mAb (RRID:AB_2106495)
- Phospho-FoxO1 (Ser256) Antibody (RRID:AB_329831)
- p44/42 MAPK (Erk1/2) Antibody (RRID:AB_330744)
- Phospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204) (D13.14.4E) XP® Rabbit mAb (RRID:AB_2315112)
- CD19 (D4V4B) XP® Rabbit mAb (RRID:AB_2800152)
- Phospho-CD19 (Tyr531) Antibody (RRID:AB_2072836)
- Btk (D3H5) Rabbit mAb (RRID:AB_10950506)
- Phospho-Btk (Tyr223) Antibody (RRID:AB_10561017)
- BLNK (D8R3G) (RRID:AB_2756401)
- Phospho-BLNK (Tyr96) Antibody (RRID:AB_2064915)
- Beta-Tubulin Antibody (RRID:AB_2210545)
- β-Actin (13E5) Rabbit mAb (RRID:AB_2223172)
- Donkey anti-Rabbit IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 647 (RRID:AB_2536183)
- Donkey anti-Mouse IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 555 (RRID:AB_2536180)
- Monoclonal ANTI-FLAG® M2 antibody produced in mouse (RRID:AB_262044)
- Akt Antibody (RRID:AB_329827)
- Phospho-Akt (Thr308) (D25E6) XP® Rabbit mAb (RRID:AB_2629447)
- Phospho-Akt (Ser473) Antibody (RRID:AB_329825)
- Mouse Anti-Phosphotyrosine 4g10?? platinum , Unconjugated (RRID:AB_916371)
Associated grants
- Agency: NCI NIH HHS, United States
Id: R01 CA240910 - Agency: NCI NIH HHS, United States
Id: R01 CA213138 - Agency: NIAID NIH HHS, United States
Id: R01 AI118855 - Agency: NCI NIH HHS, United States
Id: R01 CA157644 - Agency: NCI NIH HHS, United States
Id: P01 CA233412 - Agency: Howard Hughes Medical Institute, United States
Id: 55108547 - Agency: NCI NIH HHS, United States
Id: R35 CA197628 - Agency: NIAID NIH HHS, United States
Id: P01 AI061093
Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
This is a list of tools and resources that we have found mentioned in this publication.
QuPath (tool)
RRID:SCR_018257
Open Source software package for digital pathology image analysis. Used for whole slide image analysis and digital pathology. Provides researchers with batch processing and scripting functionality, and extensible platform with which to develop and share new algorithms to analyze complex tissue images.
View all literature mentionsAffiniPure F(ab')2 Fragment Goat Anti-Human IgM, Fc5µ Fragment Specific (min X Bov Sr Prot) (antibody)
RRID:AB_2337553
This unknown targets Human IgM, Fc5
View all literature mentionsZap-70 (D1C10E) XP(tm) Rabbit mAb (antibody)
RRID:AB_2218656
This monoclonal targets Zap70
View all literature mentionsSyk (4D10) Mouse mAb (antibody)
RRID:AB_2799953
This monoclonal targets Syk
View all literature mentionsSyk (D3Z1E) XP Rabbit Antibody (antibody)
RRID:AB_2687924
This monoclonal targets Syk
View all literature mentionsPhospho-Zap-70 (Tyr319)/Syk (Tyr352) (65E4) Rabbit mAb (antibody)
RRID:AB_2218658
This monoclonal targets Phospho-Zap-70 (Tyr319)/Syk (Tyr352)
View all literature mentionsPLCgamma1 (D9H10) XP Rabbit mAb (antibody)
RRID:AB_10691383
This monoclonal targets PLCgamma1 (D9H10) XP Rabbit mAb
View all literature mentionsPhospho-PLCgamma1 (Tyr783) Antibody (antibody)
RRID:AB_330855
This polyclonal targets Phospho-PLCgamma1 (Tyr783)
View all literature mentionsPLCγ2 Antibody (antibody)
RRID:AB_2299586
This polyclonal targets PLCγ2 Antibody
View all literature mentionsPhospho-PLC-gamma-2 (Tyr1217) Antibody (antibody)
RRID:AB_2299548
This polyclonal targets PLCG1
View all literature mentionsNFAT2 (D15F1) Rabbit mAb (antibody)
RRID:AB_10829466
This monoclonal targets NFAT2 (D15F1) Rabbit mAb
View all literature mentionsNFAT1 (D43B1) XP Rabbit mAb (antibody)
RRID:AB_10834808
This monoclonal targets NFAT1 (D43B1) XP Rabbit mAb
View all literature mentionsHistone H3 (D1H2) XP Rabbit mAb (antibody)
RRID:AB_10544537
This monoclonal targets Histone H3 (D1H2) XP Rabbit mAb
View all literature mentionsFoxO1 (C29H4) Rabbit mAb (antibody)
RRID:AB_2106495
This monoclonal targets FoxO1 (C29H4) Rabbit mAb
View all literature mentionsPhospho-FoxO1 (Ser256) Antibody (antibody)
RRID:AB_329831
This polyclonal targets Phospho-FoxO1 (Ser256)
View all literature mentionsp44/42 MAPK (Erk1/2) Antibody (antibody)
RRID:AB_330744
This polyclonal targets p44/42 MAPK (Erk1/2)
View all literature mentionsPhospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204) (D13.14.4E) XP® Rabbit mAb (antibody)
RRID:AB_2315112
This monoclonal targets Phospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204)
View all literature mentionsCD19 (D4V4B) XP® Rabbit mAb (antibody)
RRID:AB_2800152
This monoclonal targets CD19
View all literature mentionsPhospho-CD19 (Tyr531) Antibody (antibody)
RRID:AB_2072836
This polyclonal targets CD19
View all literature mentionsBtk (D3H5) Rabbit mAb (antibody)
RRID:AB_10950506
This monoclonal targets Btk (D3H5) Rabbit mAb
View all literature mentionsPhospho-Btk (Tyr223) Antibody (antibody)
RRID:AB_10561017
This polyclonal targets Phospho-Btk (Tyr223)
View all literature mentionsPhospho-BLNK (Tyr96) Antibody (antibody)
RRID:AB_2064915
This unknown targets BLNK, phospho (Tyr96)
View all literature mentionsBeta-Tubulin Antibody (antibody)
RRID:AB_2210545
This polyclonal targets Beta-Tubulin
View all literature mentionsβ-Actin (13E5) Rabbit mAb (antibody)
RRID:AB_2223172
This monoclonal targets beta-Actin
View all literature mentionsDonkey anti-Rabbit IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 647 (antibody)
RRID:AB_2536183
This polyclonal secondary targets IgG (H+L)
View all literature mentionsDonkey anti-Mouse IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 555 (antibody)
RRID:AB_2536180
This polyclonal secondary targets IgG (H+L)
View all literature mentionsMonoclonal ANTI-FLAG® M2 antibody produced in mouse (antibody)
RRID:AB_262044
This monoclonal targets FLAG
View all literature mentionsPhospho-Akt (Thr308) (D25E6) XP® Rabbit mAb (antibody)
RRID:AB_2629447
This monoclonal targets
View all literature mentionsPhospho-Akt (Ser473) Antibody (antibody)
RRID:AB_329825
This polyclonal targets Phospho-Akt (Ser473)
View all literature mentionsMouse Anti-Phosphotyrosine 4g10?? platinum , Unconjugated (antibody)
RRID:AB_916371
This unknown targets Phosphotyrosine
View all literature mentionsU266B1 (cell line)
RRID:CVCL_0566
Cell line U266B1 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsLP-1 (cell line)
RRID:CVCL_0012
Cell line LP-1 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsJJN-3 (cell line)
RRID:CVCL_2078
Cell line JJN-3 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsL-428 (cell line)
RRID:CVCL_1361
Cell line L-428 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsL-1236 (cell line)
RRID:CVCL_2096
Cell line L-1236 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsSU-DHL-4 (cell line)
RRID:CVCL_0539
Cell line SU-DHL-4 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsSU-DHL-2 (cell line)
RRID:CVCL_9550
Cell line SU-DHL-2 is a Cancer cell line with a species of origin Homo sapiens
View all literature mentionsOCI-Ly7 (cell line)
RRID:CVCL_1881
Cell line OCI-Ly7 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsOCI-Ly3 (cell line)
RRID:CVCL_8800
Cell line OCI-Ly3 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsToledo (cell line)
RRID:CVCL_3611
Cell line Toledo is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsDaudi (cell line)
RRID:CVCL_0008
Cell line Daudi is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsRamos (cell line)
RRID:CVCL_0597
Cell line Ramos is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsRaji (cell line)
RRID:CVCL_0511
Cell line Raji is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsZ-138 (cell line)
RRID:CVCL_B077
Cell line Z-138 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsMino (cell line)
RRID:CVCL_1872
Cell line Mino is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsJURL-MK2 (cell line)
RRID:CVCL_2087
Cell line JURL-MK2 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsKasumi-2 (cell line)
RRID:CVCL_0590
Cell line Kasumi-2 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsRCH-ACV (cell line)
RRID:CVCL_1851
Cell line RCH-ACV is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentions697 (cell line)
RRID:CVCL_0079
Cell line 697 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsTOM-1 (cell line)
RRID:CVCL_1895
Cell line TOM-1 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsSUP-B15 (cell line)
RRID:CVCL_0103
Cell line SUP-B15 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsReh (cell line)
RRID:CVCL_1650
Cell line Reh is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsRS4;11 (cell line)
RRID:CVCL_0093
Cell line RS4;11 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsSEM (cell line)
RRID:CVCL_0095
Cell line SEM is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsKOPN-8 (cell line)
RRID:CVCL_1866
Cell line KOPN-8 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentions
NOD.Cg-KitW-41J Tyr<+ Prkdc Il2rg/ThomJ (organism)
RRID:IMSR_JAX:026622
Mus musculus with name NOD.Cg-KitW-41J Tyr<+ Prkdc
B6.C(Cg)-Cd79atm1(cre)Reth/EhobJ (organism)
RRID:IMSR_JAX:020505
Mus musculus with name B6.C(Cg)-Cd79atm1(cre)Reth/EhobJ from IMSR.
View all literature mentions
