MNKs act as a regulatory switch for eIF4E1 and eIF4E3 driven mRNA translation in DLBCL.
The phosphorylation of eIF4E1 at serine 209 by MNK1 or MNK2 has been shown to initiate oncogenic mRNA translation, a process that favours cancer development and maintenance. Here, we interrogate the MNK-eIF4E axis in diffuse large B-cell lymphoma (DLBCL) and show a distinct distribution of MNK1 and MNK2 in germinal centre B-cell (GCB) and activated B-cell (ABC) DLBCL. Despite displaying a differential distribution in GCB and ABC, both MNKs functionally complement each other to sustain cell survival. MNK inhibition ablates eIF4E1 phosphorylation and concurrently enhances eIF4E3 expression. Loss of MNK protein itself downregulates total eIF4E1 protein level by reducing eIF4E1 mRNA polysomal loading without affecting total mRNA level or stability. Enhanced eIF4E3 expression marginally suppresses eIF4E1-driven translation but exhibits a unique translatome that unveils a novel role for eIF4E3 in translation initiation. We propose that MNKs can modulate oncogenic translation by regulating eIF4E1-eIF4E3 levels and activity in DLBCL.
Marlene &Stewart Greenebaum Cancer Center, Department of Medicine, University of Maryland, Baltimore, Maryland 21201, USA.
Ari L
AL
Landon
1] Marlene &Stewart Greenebaum Cancer Center, Department of Medicine, University of Maryland, Baltimore, Maryland 21201, USA [2] Veterans Administration Medical Center, Baltimore, Maryland 21201, USA.
Parameswary A
PA
Muniandy
Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Amol C
AC
Shetty
Gene Expression and Genomics Unit, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
Elin
E
Lehrmann
Institute for Research in Immunology and Cancer, Department of Pathology and Cell Biology, Université de Montréal, Montréal, Québec, Canada H3T 1J4.
Laurent
L
Volpon
1] Marlene &Stewart Greenebaum Cancer Center, Department of Medicine, University of Maryland, Baltimore, Maryland 21201, USA [2] Veterans Administration Medical Center, Baltimore, Maryland 21201, USA.
Simone
S
Houng
Gene Expression and Genomics Unit, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
Yongqing
Y
Zhang
1] Marlene &Stewart Greenebaum Cancer Center, Department of Medicine, University of Maryland, Baltimore, Maryland 21201, USA [2] Veterans Administration Medical Center, Baltimore, Maryland 21201, USA.
Bojie
B
Dai
Marlene &Stewart Greenebaum Cancer Center, Department of Medicine, University of Maryland, Baltimore, Maryland 21201, USA.
Raymond
R
Peroutka
Marlene &Stewart Greenebaum Cancer Center, Department of Medicine, University of Maryland, Baltimore, Maryland 21201, USA.
Krystyna
K
Mazan-Mamczarz
Marlene &Stewart Greenebaum Cancer Center, Department of Medicine, University of Maryland, Baltimore, Maryland 21201, USA.
James
J
Steinhardt
Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Anup
A
Mahurkar
Gene Expression and Genomics Unit, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
Kevin G
KG
Becker
Institute for Research in Immunology and Cancer, Department of Pathology and Cell Biology, Université de Montréal, Montréal, Québec, Canada H3T 1J4.
Katherine L
KL
Borden
1] Marlene &Stewart Greenebaum Cancer Center, Department of Medicine, University of Maryland, Baltimore, Maryland 21201, USA [2] Veterans Administration Medical Center, Baltimore, Maryland 21201, USA.
Ronald B
RB
Gartenhaus
D045744:Cell Line, Tumor; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism
D039561:Eukaryotic Initiation Factor-4E; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; C000603324:eIF4E3 protein, human; C491395:MKNK1 protein, human; C486342:MKNK2 protein, human; D017346:Protein Serine-Threonine Kinases