SYK is activated by mutated MYD88 and drives pro-survival signaling in MYD88 driven B-cell lymphomas.

Cell Line, Tumor Humans Lymphoma, Large B-Cell, Diffuse / genetics Mutation Myeloid Differentiation Factor 88 / genetics Signal Transduction Syk Kinase / genetics

Journal

Blood cancer journal
ISSN: 2044-5385
Titre abrégé: Blood Cancer J
Pays: United States
ID NLM: 101568469

Informations de publication

Date de publication:
31 01 2020
Historique:
received: 26 08 2019
accepted: 13 01 2020
revised: 30 12 2019
entrez: 2 2 2020
pubmed: 2 2 2020
medline: 25 9 2020
Statut: epublish

Résumé

Activating MYD88 mutations promote pro-survival signaling through BTK and HCK, both targets of ibrutinib. Despite high response rates, complete responses to ibrutinib are lacking, and other MYD88 triggered pro-survival pathways may contribute to primary drug resistance. B-cell receptor (BCR) signaling has been observed in lymphomas driven by mutated MYD88, even without activating the BCR pathway mutations. We identified activated SYK (p-SYK), a component of BCR in complex with MYD88 in MYD88-mutated WM and ABC DLBCL lymphoma cells. Confocal microscopy confirmed co-localization of MYD88 with SYK in MYD88-mutated cells. Knockdown of MYD88 or use of a MYD88 signaling inhibitor abrogated SYK activation, while expression of mutated but not wild-type MYD88 amplified p-SYK in MYD88-mutated and wild-type lymphoma cells. Knockdown of SYK or use of inhibitors targeting SYK blocked p-STAT3 and p-AKT signaling in MYD88-mutated cells. Cell viability analysis showed that combining ibrutinib and SYK inhibitors triggered synthetic killing of MYD88-mutated lymphoma cells. Our findings extend the spectrum of mutated MYD88 pro-survival signaling to include SYK directed BCR cross talk in MYD88-mutated lymphomas. Targeting SYK in combination with ibrutinib produces synthetic lethality, providing a framework for the clinical investigation of ibrutinib with SYK inhibitors in MYD88-mutated lymphomas.

Identifiants

DOI: 10.1038/s41408-020-0277-6 PMID: 32005797 PMC: PMC6994488
pubmed: 32005797
doi: 10.1038/s41408-020-0277-6
pii: 10.1038/s41408-020-0277-6
pmc: PMC6994488
doi:

Substances chimiques

MYD88 protein, human 0
Myeloid Differentiation Factor 88 0
SYK protein, human EC 2.7.10.2
Syk Kinase EC 2.7.10.2

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

12

Subventions

Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA100707
Pays : United States

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Auteurs

Manit Munshi (M)

Bing Center for Waldenstrom's Macroglobulinemia, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.

Xia Liu (X)

Bing Center for Waldenstrom's Macroglobulinemia, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.

Jiaji G Chen (JG)

Bing Center for Waldenstrom's Macroglobulinemia, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.

Lian Xu (L)

Bing Center for Waldenstrom's Macroglobulinemia, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.

Nickolas Tsakmaklis (N)

Bing Center for Waldenstrom's Macroglobulinemia, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.

Maria G Demos (MG)

Bing Center for Waldenstrom's Macroglobulinemia, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.

Amanda Kofides (A)

Bing Center for Waldenstrom's Macroglobulinemia, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.

Maria Luisa Guerrera (ML)

Bing Center for Waldenstrom's Macroglobulinemia, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.

Cristina Jimenez (C)

Bing Center for Waldenstrom's Macroglobulinemia, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.

Gloria G Chan (GG)

Bing Center for Waldenstrom's Macroglobulinemia, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.

Zachary R Hunter (ZR)

Bing Center for Waldenstrom's Macroglobulinemia, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
Department of Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
ORCID: 0000-0002-1689-1691

M Lia Palomba (ML)

Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Kimon V Argyropoulos (KV)

Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Kirsten Meid (K)

Bing Center for Waldenstrom's Macroglobulinemia, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.

Andrew Keezer (A)

Bing Center for Waldenstrom's Macroglobulinemia, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.

Joshua Gustine (J)

Bing Center for Waldenstrom's Macroglobulinemia, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.

Toni Dubeau (T)

Bing Center for Waldenstrom's Macroglobulinemia, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
Department of Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.

Jorge J Castillo (JJ)

Bing Center for Waldenstrom's Macroglobulinemia, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
Department of Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
ORCID: 0000-0001-9490-7532

Christopher J Patterson (CJ)

Bing Center for Waldenstrom's Macroglobulinemia, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.

Jinhua Wang (J)

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.

Sara J Buhrlage (SJ)

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.

Nathanael S Gray (NS)

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.

Steven P Treon (SP)

Bing Center for Waldenstrom's Macroglobulinemia, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. steven_treon@dfci.harvard.edu.
Department of Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. steven_treon@dfci.harvard.edu.

Guang Yang (G)

Bing Center for Waldenstrom's Macroglobulinemia, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
Department of Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.

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Classifications MeSH

questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › SYK is activated by mutated MYD88 and drives...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › SYK is activated by mutated MYD88 and drives...
questionsmedicales.fr › Maladies du système immunitaire › Syndromes immunoprolifératifs › Syndromes lymphoprolifératifs › Lymphomes › Lymphome malin non hodgkinien › Lymphome B › Lymphome B diffus à grandes cellules › SYK is activated by mutated MYD88 and drives...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › SYK is activated by mutated MYD88 and drives...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines adaptatrices de la transduction du signal › Facteur de différenciation myéloïde-88 › SYK is activated by mutated MYD88 and drives...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › SYK is activated by mutated MYD88 and drives...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-tyrosine kinases › Syk kinase › SYK is activated by mutated MYD88 and drives...