Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2094-2111.e9 |
| Journal | Molecular Cell |
| Volume | 81 |
| Issue number | 10 |
| DOIs | |
| State | Published - May 20 2021 |
Keywords
- Anergy
- B cell selection
- Kinases
- Leukemia
- NFAT
- Tolerance
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology
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Developmental partitioning of SYK and ZAP70 prevents autoimmunity and cancer. / Sadras, Teresa; Martin, Mickaël; Kume, Kohei; Robinson, Mark E.; Saravanakumar, Supraja; Lenz, Gal; Chen, Zhengshan; Song, Joo Y.; Siddiqi, Tanya; Oksa, Laura; Knapp, Anne Marie; Cutler, Jevon; Cosgun, Kadriye Nehir; Klemm, Lars; Ecker, Veronika; Winchester, Janet; Ghergus, Dana; Soulas-Sprauel, Pauline; Kiefer, Friedemann; Heisterkamp, Nora; Pandey, Akhilesh; Ngo, Vu; Wang, Lili; Jumaa, Hassan; Buchner, Maike; Ruland, Jürgen; Chan, Wing Chung; Meffre, Eric; Martin, Thierry; Müschen, Markus.
In: Molecular Cell, Vol. 81, No. 10, 20.05.2021, p. 2094-2111.e9.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Developmental partitioning of SYK and ZAP70 prevents autoimmunity and cancer
AU - Sadras, Teresa
AU - Martin, Mickaël
AU - Kume, Kohei
AU - Robinson, Mark E.
AU - Saravanakumar, Supraja
AU - Lenz, Gal
AU - Chen, Zhengshan
AU - Song, Joo Y.
AU - Siddiqi, Tanya
AU - Oksa, Laura
AU - Knapp, Anne Marie
AU - Cutler, Jevon
AU - Cosgun, Kadriye Nehir
AU - Klemm, Lars
AU - Ecker, Veronika
AU - Winchester, Janet
AU - Ghergus, Dana
AU - Soulas-Sprauel, Pauline
AU - Kiefer, Friedemann
AU - Heisterkamp, Nora
AU - Pandey, Akhilesh
AU - Ngo, Vu
AU - Wang, Lili
AU - Jumaa, Hassan
AU - Buchner, Maike
AU - Ruland, Jürgen
AU - Chan, Wing Chung
AU - Meffre, Eric
AU - Martin, Thierry
AU - Müschen, Markus
N1 - Funding Information: We would like to thank Theresa Kadlecek and Arthur Weiss (University of California, San Francisco [UCSF]), David Weinstock (Harvard University and Dana-Farber Cancer Institute [DFCI]), and Vaidehi Nagarajan (City of Hope) for their support and critical discussion; Lauren Kim-Sing; current and former members of the Müschen laboratory; and A.S. Korganow, F. Gros, and L. Vallat and the former members of the UPR CNRS 3572 for their support and help with experimental work. We would also like to acknowledge Aimin Li and Michael Nelson (City of Hope) for their technical support with tissue microarrays (TMAs) and microscopy and Quan-Zhen Li (University of Texas Southwestern Medical Center) for their technical support with the autoantigen microarrays. Research in the Müschen laboratory is funded by the NIH through a National Cancer Institute (NCI) Outstanding Investigator Award (R35CA197628, R01CA157644, R01CA213138, and P01CA233412 to M. Müschen), the Howard Hughes Medical Institute (HHMI-55108547 to M. Müschen), the Arthur H. and Isabel Bunker Chair in Hematology (to M. Müschen), the Blood Cancer Discoveries Grant Program through the Leukemia & Lymphoma Society, the Mark Foundation For Cancer Research, the Paul G. Allen Frontiers Group, and the V Foundation for Cancer Research (T2018-003B to M. Müschen). This work was supported by grant funding from the NIH/National Institute of Allergy and Infectious Diseases (NIAID) (AI061093 and AI118855) and by a TIL grant from the Lupus Research Alliance to E.M. The generation of the Zap70Mb1-Cre-knockin model was supported by the foundations Alsace contre le Cancer, Groupe Pasteur Mutualité, and CSL Behring. T. Sadras is a fellow of the Lymphoma Research Foundation. M. Müschen is a Howard Hughes Medical Institute (HHMI) Faculty Scholar. T. Sadras performed in vitro experiments, developed leukemia mouse models and humanized mice, and analyzed data. M. Martin established Zap70Mb1-Cre colonies, performed characterization of mouse model, and contributed to writing the manuscript. M.E.R. provided statistical assistance and performed all bioinformatics analyses. K.K. assisted with time-lapse calcium experiments. A.M.K. D.G. and P.S.-S. assisted with generation and fluorescence-activated cell sorting (FACS) analysis of Zap70Mb1-Cre mice. S.S. Z.C. L.O. K.N.C. L.K. V.E. and J.W. performed experiments and assisted with in vivo models. G.L. provided expertise and assistance with single-cell western blot experiments. J.C. and A.P. performed BioID experiments and analyzed data. T. Siddiqi provided CLL patient samples and critical discussions. J.Y.S. and W.-C.C. performed TMA analysis and interpretation of results. F.K. N.H. and H.J. provided mice, critical discussions, and editing of the manuscript. V.N. L.W. M.B. and J.R. provided critical discussions and editing of the manuscript. E.M. T.M. and M. Müschen supervised the study, provided mentorship, and secured funding. T. Sadras and M. Müschen wrote the manuscript with assistance from all co-authors. M. Müschen led the project and developed concept of “autoimmunity checkpoints.”, E.M. is an advisor for and receives funding from AbbVie, Inc. All other authors declare no competing interests. Funding Information: We would like to thank Theresa Kadlecek and Arthur Weiss (University of California, San Francisco [UCSF]), David Weinstock (Harvard University and Dana-Farber Cancer Institute [DFCI]), and Vaidehi Nagarajan (City of Hope) for their support and critical discussion; Lauren Kim-Sing; current and former members of the Müschen laboratory; and A.S. Korganow, F. Gros, and L. Vallat and the former members of the UPR CNRS 3572 for their support and help with experimental work. We would also like to acknowledge Aimin Li and Michael Nelson (City of Hope) for their technical support with tissue microarrays (TMAs) and microscopy and Quan-Zhen Li (University of Texas Southwestern Medical Center) for their technical support with the autoantigen microarrays. Research in the Müschen laboratory is funded by the NIH through a National Cancer Institute (NCI) Outstanding Investigator Award ( R35CA197628 , R01CA157644 , R01CA213138 , and P01CA233412 to M. Müschen), the Howard Hughes Medical Institute (HHMI- 55108547 to M. Müschen), the Arthur H. and Isabel Bunker Chair in Hematology (to M. Müschen), the Blood Cancer Discoveries Grant Program through the Leukemia & Lymphoma Society , the Mark Foundation For Cancer Research , the Paul G. Allen Frontiers Group , and the V Foundation for Cancer Research ( T2018-003B to M. Müschen). This work was supported by grant funding from the NIH /National Institute of Allergy and Infectious Diseases (NIAID) (AI061093 and AI118855) and by a TIL grant from the Lupus Research Alliance to E.M. The generation of the Zap70 Mb1-Cre -knockin model was supported by the foundations Alsace contre le Cancer , Groupe Pasteur Mutualité , and CSL Behring . T. Sadras is a fellow of the Lymphoma Research Foundation. M. Müschen is a Howard Hughes Medical Institute (HHMI) Faculty Scholar. Publisher Copyright: © 2021 Elsevier Inc.
PY - 2021/5/20
Y1 - 2021/5/20
N2 - 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.
AB - 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.
KW - Anergy
KW - B cell selection
KW - Kinases
KW - Leukemia
KW - NFAT
KW - Tolerance
UR - http://www.scopus.com/inward/record.url?scp=85105953540&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85105953540&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2021.03.043
DO - 10.1016/j.molcel.2021.03.043
M3 - Article
C2 - 33878293
AN - SCOPUS:85105953540
VL - 81
SP - 2094-2111.e9
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 10
ER -