Homeobox NKX2-3 promotes marginal-zone lymphomagenesis by activating B-cell receptor signalling and shaping lymphocyte dynamics.
NKX2 homeobox family proteins have a role in cancer development. Here we show that NKX2-3 is overexpressed in tumour cells from a subset of patients with marginal-zone lymphomas, but not with other B-cell malignancies. While Nkx2-3-deficient mice exhibit the absence of marginal-zone B cells, transgenic mice with expression of NKX2-3 in B cells show marginal-zone expansion that leads to the development of tumours, faithfully recapitulating the principal clinical and biological features of human marginal-zone lymphomas. NKX2-3 induces B-cell receptor signalling by phosphorylating Lyn/Syk kinases, which in turn activate multiple integrins (LFA-1, VLA-4), adhesion molecules (ICAM-1, MadCAM-1) and the chemokine receptor CXCR4. These molecules enhance migration, polarization and homing of B cells to splenic and extranodal tissues, eventually driving malignant transformation through triggering NF-κB and PI3K-AKT pathways. This study implicates oncogenic NKX2-3 in lymphomagenesis, and provides a valid experimental mouse model for studying the biology and therapy of human marginal-zone B-cell lymphomas.
Division of Hemato-Oncology, Center for Applied Medical Research CIMA, University of Navarra, IDISNA, Pamplona 31008, Spain.
Eloy F
EF
Robles
Division of Hemato-Oncology, Center for Applied Medical Research CIMA, University of Navarra, IDISNA, Pamplona 31008, Spain.
Maria
M
Mena-Varas
Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB)-CSIC, Madrid 28049, Spain.
Laura
L
Barrio
Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB)-CSIC, Madrid 28049, Spain.
Sara V
SV
Merino-Cortes
Department of Immunology and Biotechnology, Szentágothai Research Center, University of Pécs, Pécs H-7624, Hungary.
Péter
P
Balogh
Division of Molecular Histopathology, Department of Pathology, Cambridge University, Cambridge CB2 1QP, UK.
Ming-Qing
MQ
Du
MRC Toxicology Unit and Ernest and Helen Scott Haematological Research Institute, Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester LE2 7LX, UK.
Takashi
T
Akasaka
Department of Haematology, Royal Bournemouth Hospital, Bournemouth BH7 7DW, UK.
Anton
A
Parker
Division of Hemato-Oncology, Center for Applied Medical Research CIMA, University of Navarra, IDISNA, Pamplona 31008, Spain.
Sergio
S
Roa
Department of Hematology, Clinica Universidad de Navarra, IDISNA, Pamplona 31008, Spain.
Carlos
C
Panizo
Institute of Human Genetics, Christian-Albrechts-University Kiel &University Hospital Schleswig-Holstein, Campus Kiel, Kiel 24105, Germany.
Idoia
I
Martin-Guerrero
Institute of Human Genetics, Christian-Albrechts-University Kiel &University Hospital Schleswig-Holstein, Campus Kiel, Kiel 24105, Germany.
Reiner
R
Siebert
Bio-informatic Unit, Department of Genomics and Proteomics, Center for Applied Medical Research CIMA, University of Navarra, IDISNA, Pamplona 31008, Spain.
Victor
V
Segura
Division of Hemato-Oncology, Center for Applied Medical Research CIMA, University of Navarra, IDISNA, Pamplona 31008, Spain.
Xabier
X
Agirre
Division of Hemato-Oncology, Center for Applied Medical Research CIMA, University of Navarra, IDISNA, Pamplona 31008, Spain.
Laura
L
Macri-Pellizeri
Division of Hemato-Oncology, Center for Applied Medical Research CIMA, University of Navarra, IDISNA, Pamplona 31008, Spain.
Beatriz
B
Aldaz
Division of Hemato-Oncology, Center for Applied Medical Research CIMA, University of Navarra, IDISNA, Pamplona 31008, Spain.
Amaia
A
Vilas-Zornoza
Division of Molecular Histopathology, Department of Pathology, Cambridge University, Cambridge CB2 1QP, UK.
Shaowei
S
Zhang
Division of Molecular Histopathology, Department of Pathology, Cambridge University, Cambridge CB2 1QP, UK.
Sarah
S
Moody
Department of Genetics, School of Medicine, University of Navarra, IDISNA, Pamplona 31008, Spain.
Maria Jose
MJ
Calasanz
Centre for Translation Cell and Tissue Research, KU Leuven, Leuven 3000, Belgium.
Thomas
T
Tousseyn
Department of Pathology, Institut Universitaire du Cancer de Toulouse-Oncopole, Labex TOUCAN and CRCT INSERM U1037, Toulouse F-31053, France.
Cyril
C
Broccardo
Department of Pathology, Institut Universitaire du Cancer de Toulouse-Oncopole, Labex TOUCAN and CRCT INSERM U1037, Toulouse F-31053, France.
Pierre
P
Brousset
Centro de Biologia Molecular Severo Ochoa, CSIC/Universidad Autonoma, Madrid 28049, Spain.
Elena
E
Campos-Sanchez
Centro de Biologia Molecular Severo Ochoa, CSIC/Universidad Autonoma, Madrid 28049, Spain.
Cesar
C
Cobaleda
Experimental Therapeutics and Translational Oncology Program, Institute of Molecular and Cellular Biology of Cancer, CSIC/University of Salamanca; and Institute of Biomedical Research of Salamanca (IBSAL), Salamanca 37007, Spain.
Isidro
I
Sanchez-Garcia
Molecular Genetics Unit, University Hospital Marques de Valdecilla and IFIMAV, Santander 39011, Spain.
Jose Luis
JL
Fernandez-Luna
Hematology Department, Hospital San Pedro, Logroño, 26006, La Rioja, Spain.
Ricardo
R
Garcia-Muñoz
Department of Hematology, Complejo Hospitalario de Navarra, Servicio Navarro de Salud, IDISNA, Pamplona 31008, Spain.
Esther
E
Pena
Department of Pathology, Cancer Research Program, Institut Municipal d'Investigacions Mèdiques (IMIM), Hospital del Mar, Barcelona 08003, Spain.
Beatriz
B
Bellosillo
Department of Clinical Hematology, Cancer Research Program, Institut Municipal d'Investigacions Mèdiques (IMIM), Hospital del Mar, Barcelona 08003, Spain.
Antonio
A
Salar
Department of Hematology, ICO-Hospital Universitari Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute, Universitat Autònoma de Barcelona, Badalona 08916, Spain.
Maria Joao
MJ
Baptista
Department of Hematology, IBSAL-University Hospital and IBMCC-CSIC, University of Salamanca, Salamanca 37007, Spain.
Jesús Maria
JM
Hernandez-Rivas
Department of Hematology, IBSAL-University Hospital and IBMCC-CSIC, University of Salamanca, Salamanca 37007, Spain.
Marcos
M
Gonzalez
Department of Hematology, Hospital Clinico, INCLIVA Biomedical Research Institute, University of Valencia, Valencia 46010, Spain.
Maria Jose
MJ
Terol
Department of Hematology, Hospital Clinico, INCLIVA Biomedical Research Institute, University of Valencia, Valencia 46010, Spain.
Joan
J
Climent
Department of Pathology, Hospital Clinico, University of Valencia, Valencia 46010, Spain.
Antonio
A
Ferrandez
Centre for Translation Cell and Tissue Research, KU Leuven, Leuven 3000, Belgium.
Xavier
X
Sagaert
Department of Medicine/Hematology-Oncology, Weill Cornell Medical College, New York, New York 10065, USA.
Ari M
AM
Melnick
Division of Hemato-Oncology, Center for Applied Medical Research CIMA, University of Navarra, IDISNA, Pamplona 31008, Spain.|Department of Hematology, Clinica Universidad de Navarra, IDISNA, Pamplona 31008, Spain.
Felipe
F
Prosper
Department of Haematology, Royal Bournemouth Hospital, Bournemouth BH7 7DW, UK.
David G
DG
Oscier
Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB)-CSIC, Madrid 28049, Spain.
Yolanda R
YR
Carrasco
MRC Toxicology Unit and Ernest and Helen Scott Haematological Research Institute, Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester LE2 7LX, UK.
Martin J S
MJ
Dyer
Division of Hemato-Oncology, Center for Applied Medical Research CIMA, University of Navarra, IDISNA, Pamplona 31008, Spain.
Jose A
JA
Martinez-Climent
D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D008214:Lymphocytes / Q000378:metabolism*; D008221:Lymphoid Tissue / Q000378:metabolism; D018442:Lymphoma, B-Cell, Marginal Zone / Q000235:genetics* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D011947:Receptors, Antigen, B-Cell / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D000072377:Syk Kinase / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
D015815:Cell Adhesion Molecules; D018398:Homeodomain Proteins; C534957:NKX2-3 protein, human; C522706:Nkx2.3 protein, mouse; D011947:Receptors, Antigen, B-Cell; D014157:Transcription Factors; D000072377:Syk Kinase