Sup. Fig. 1. Densitometry and IHC analysis. (a) Densitometry analysis showing

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1 # # # # # # # Supplemental Figure a.5# *" b c MNK# MNK#.5# p)eif4e# MNK# *" RelaAve#protein#level#.0# 0.5# 0.0# *" *" *" *" GM084# SUDHL)6# Pfeiffer# HLY)# TMD8# RelaAve#protein#level#.0# 0.5# 0.0# *" *" *" EV#NT# EV#MKD# MWT#NT# MWT# MKD# RelaAve#protein#level#.5#.0# 0.5# 0.0# p)eif4e# *" *" MNK# *" EV# EV#MKD# MWT#NT# MWT# MKD# d Percentage#of#total#TMA#cores# 00# 80# 60# 40# 0# 0# Normal#LN# GCB# ABC# NegaAve# Low# Moderate# High# Lymphoma#Assues# Normal#Assues# e f RelaAve#phospho)eIF4E(S09)# RelaAve#phospho)eIF4E(S09)#.5#.0# 0.5# 0.0#.5#.0# 0.5# 0.0# Vehicle# AZD644# HLY)# GM084# Pfeiffer# Vehicle# *" VX70# *" HLY)# GM084# Pfeiffer# RelaAve#phospho)ERK# RelaAve#phospho)MNK/#.5#.0# 0.5# 0.0#.5# 0.0# Vehicle# AZD644# *" *" *" HLY)# GM084# Pfeiffer# Vehicle# VX70#.0# *" *" *" 0.5# HLY)# GM084# Pfeiffer# Sup. Fig.. Densitometry and IHC analysis. (a) Densitometry analysis showing relative band intensity of MNK and MNK to GAPDH from immunoblot in Fig.b. (b) Densitometry analysis showing relative band intensity of p-eif4e (S09) and MNK from immunoblot in Fig.g. (c) Densitometry analysis showing relative band intensity of p-eif4e (S09) and MNK from immunoblot in Fig.h. (d) Top: Bar graph showing percentage of tissue microarray (TMA) cores stained for p-eif4e level in normal lymph node (LN), ABC-DLBCL and GCB-DLBCL samples. Bottom: Broad field photographic image illustrating p-eif4e IHC staining in TMA slides with normal and lymphoma sample mapping. (e) Densitometry analysis showing relative band intensity of phosphoeif4e (S09) and phospho-erk to GAPDH in HLY- cells from immunoblot in Fig.a. (f) Densitometry analysis showing relative band intensity of phospho-eif4e (S09) and phospho-mnk/ to GAPDH in HLY- cells from immunoblot in Fig.b. Values are mean of three independent measurements (mean ± S.D., *p-value of student t-test < 0.05).

2 Supplemental Figure a Vehicle# AZD644# Vehicle# AZD644# Vehicle# AZD644# Vehicle# AZD644# Vehicle# AZD644# Vehicle# AZD644# p6eif4e#(s09)# Total#eIF4E# p6erk#(t0/y04)# ERK# GAPDH# HLY6# GM084# Pfeiffer# HLY6# GM084# Pfeiffer# 45#min# 4#hrs# b Vehicle# AZD644# no.76# Vehicle# AZD644# no.76# Vehicle# AZD644# no.76# Vehicle# AZD644# no.76# p6eif4e#(s09)# Total#eIF4E# p6erk#(t0/y04)# ERK# GAPDH# HLY6# Pfeiffer# HLY6## Pfeiffer# 48#hrs# 7#hrs# Sup. Fig.. MEK and ERK inhibition does not impact eif4e phosphorylation. (a) Western blot of cell lysates from HLY-, GM084 and Pfeiffer cell lines treated with 00 nm of MEK inhibitor, AZD644 for 45 min or 4 hrs, and probed for total and phosphoeif4e, total and phospho-erk and GAPDH. (b) Western blot showing cell lysates from HLY- and Pfeiffer cell lines treated with 00 nm of MEK inhibitor or 0 µm of ERK inhibitor, no.76 for 48 or 7 hrs, and probed for total and phospho-eif4e, total and phospho-erk and GAPDH. All blots shown are representative of at least three experimental replicates.

3 CGP5780(+(FTY70( Cercosporamide(+(FTY70( FTY70( CGP57380( Cercosporamide( Vehicle( CGP5780(+(FTY70( Cercosporamide(+(FTY70( FTY70( CGP57380( Cercosporamide( Vehicle( CGP5780(+(FTY70( Cercosporamide(+(FTY70( FTY70( CGP57380( Cercosporamide( Vehicle( Supplemental Figure 3 p/eif4e((s09)( p/erk((t0/y04)( p/p38((t80/y8)( Total(eIF4E( Total(ERK( Total(p38( GAPDH( GM084(4(hrs( HLY/(4(hrs( HLY/(4(hrs( Sup. Fig.3. PPA activation using FTY70 did not affect eif4e phosphorylation. Western blot of cell lysates from GM084 and HLY- cells treated with MNK inhibitors; CGP57380 (0 µm) or Cercosporamide (5 µm), PPA activator, FTY70 (0 µm) or in combination as indicated for 4 or 4 hrs, and probed for total and phospho-eif4e, total and phospho-erk, total and phospho-p38 and GAPDH. All blots shown are representative of at least three experimental replicates.

4 Supplemental Figure 4 a 48%hrs% %%of%max% 7%hrs% CFSE% b G0/G( S( G/M( VX70& Vx70( Vehicle( 0%( 0%( 40%( 60%( 80%( 00%( Treatment( G0/G( S( G/M( Vehicle( 63.4±0.7( 3.9±0.9( 3.8±0.( Vx70( VX70& 5.7±0.4( 4.3±.7( 5.4±.3( c Rela7ve#BrdU#incorpora7on#to#Vehicle#.#.0# 0.8# 0.6# 0.4# 0.# 0.0# Vehicle# *" VX70(00nM)# Sup. Fig.4. Effect of p38 inhibition on DLBCL cell line (a) CFSE cell proliferation assay at 48 and 7 hrs post DMSO (-) or VX70 (00 nm) (-) treatment in triplicates (one representative figure is shown in Fig.g). (b) Cell cycle analysis of HLY- cells after 7 hrs treatment with either vehicle or VX70 (00 nm), showing a marginal increase in S- phase cell populations. Values are represented as percent of total cell population (mean ± S.D., n=3). (c) BrdU incorporation ELISA assay of HLY- cells treated with vehicle ( ) or VX70, 00 nm ( ). Values are representative of three independent experiments (mean ± S.D., * p-value of student t-test < 0.05).

5 # # ' ' Supplemental Figure 5 a Rela%ve'total'eIF4E'Protein'.5#.0# 0.5# 0.0# NT# MNKKD# *# Empty#Vector# MNK#WT# MNK#WT# b Rela%ve'total'eIF4E'Protein'.5#.0# 0.5# 0.0# NT# MNKKD# *# Empty#Vector# MNK#WT# MNK#WT# c d Rela@ve#total#eIF4E#Protein# Untreated&.#.0# 0.8# 0.6# 0.4# 0.# 0.0# GM084#NT# GM084#MOI:# GM084#MOI:5# NT& MOI:5& *" *" Pfeiffer#NT# Pfeiffer#MOI:# Pfeiffer#MOI:5# Jurkat#NT# Jurkat#MOI:# Jurkat#MOI:5# HCT6#NT# HCT6#MOI:# HCT6#MOI:5# Rela@ve#total#MNK#Protein#.#.0# 0.8# 0.6# 0.4# 0.# 0.0# GM084#NT# GM084#MOI:# GM084#MOI:5# *" *" Pfeiffer#NT# Pfeiffer#MOI:# Pfeiffer#MOI:5# Jurkat#NT# Jurkat#MOI:# Jurkat#MOI:5# *" HCT6#NT# HCT6#MOI:# HCT6#MOI:5# *" MNK& eif4e& GAPDH& HLY$& Sup. Fig. 5. Densitometry analysis and eif4e knockdown. (a-b) Densitometry analysis showing relative band intensity to GAPDH of total eif4e in HLY- cells treated with either NT ( ), (a) MNK or (b) MNK KD shrna ( ) (MOI=0) from (a) Fig.3k or (b) Fig.3l. (c) Densitometry analysis showing relative band intensity to GAPDH of total eif4e (left) and MNK (right) in HLY- cells treated with either NT ( ), MNK KD MOI: ( ), or MNK KD MOI:5 shrna ( ) from Fig.3m. All densitometry values are mean from three independent measurements (mean ± S.D., *p-value of student t-test < 0.05). (d) Western blot analysis of HLY- cells untreated, with NT shrna or MNK KD shrna (TRCN ) and probed for MNK and eif4e.

6 Supplemental Figure 6 a Empty&Vector& eif4e&fl& eif4e&s09d& eif4e&s09a& eif4e3&fl& eif4e3&d99& MNK&WT& MNK&TD& MNK&AA& MNK&WT& b IgG( Empty(Vector( eif4e(fl( eif4e(s09d( eif4e(s09a( eif4e3(fl( eif4e3(d99( MNK(WT( MNK(TD( MNK(AA( MNK(WT( Input((Empty(Vector)( p.eif4e(s09)& eif4g&ip( IB:(eIF4E(! Total&eIF4E& MCL& GAPDH& Turbo.GFP& eif4e3& c CapAPD& CapAPD& Cap&Only& Empty&Vector& eif4e&fl& eif4e&s09d& eif4e&s09a& eif4e3&fl& eif4e3&d99& Input&(empty&vector)& IB:&eIF4E& IB:&eIF4E3& Sup. Fig 6. Analysis of Pfeiffer cell lines stably expressing wildtype or mutated eif4e, eif4e3, MNK and MNK (a) Western blot analysis of Pfeiffer cells transduced with various constructs as indicated and probed for total and phospho-eif4e (S09), MCL-, GAPDH, GFP and eif4e3. (b-c) Immunoblot of Pfeiffer cell lysate after (b) IP using eif4g antibody or (c) cap pull down, and probed for eif4e or eif4e3. All blots shown are representative of at least three experimental replicates.

7 Supplemental Figure 7 a GM084' ' ' Pfeiffer' SUDHL>6' Toledo' U93' HLY>' TMD8' eif4e3' GAPDH' b Empty'Vector' MNK'WT' MNK'TD' MNK'AA' MNK'WT' eif4e3' GAPDH' HLY>' Sup. Fig.7. eif4e3 expression in various cell lines and HLY- cells expressing MNK wildtype and mutant proteins (a) Western blot analysis of various DLBCL cell lines for basal levels of eif4e3 expression. (b) Western blot analysis of eif4e3 in HLY- mutant cell lines. All blots shown are representative of at least three experimental replicates.

8 Supplemental Figure 8 a b.& eif4e&kd& NT" Low" High" TRCN & HLY$& Total(eIF4E" GAPDH" Cell&Survival&(%)&.0& 0.8& 0.6& 0.4& 0.& *" *" 0.0& NT& Low& High& c NT" TRCN " Low" High" TRCN "" TRCN "" Low" High" Low" High" Low" TRCN "" High" eif4e3& d Cell&Survival&(%)&.&.0& 0.8& 0.6& 0.4& 0.& Low& High& *" *" *" *" GAPDH& 0.0& NT& TRCN & TRCN & TRCN & TRCN & Sup. Fig. 8. shrna knockdown of eif4e and eif4e3 (a) Western blot analysis of HLY- cells treated with eif4e knockdown (KD) shrna at 48 hrs post transduction, and probed for eif4e (b) Trypan blue exclusion assay for cell survival of HLY- cells with eif4e KD from Sup.Fig.8a. Values are mean ± S.D., n=3 *p-value of student t-test <0.05 (c) Western blot analysis of HLY- cells treated with various eif4e3 KD shrna as indicated, after 48 hrs post-transduction. (d) Trypan blue exclusion assay for cell survival of HLY- cells treat with various eif4e3 KD shrnas, 48 hrs post-transduction from Sup. Fig.8c in comparison to NT treated cells (n ). Values are mean ± S.D., n=3, *p-value of student t-test < 0.05.

9 Supplemental Figure 9 a EV# eif4e# EV# eif4e# b NT# eif4e#kd# BTK# YY# CDK6# Total#eIF4E# GAPDH# BTK# YY# CDK6# Total#eIF4E# GAPDH# Pfeiffer# GM084# SUDHLD# Sup. Fig. 9. NF-κB targets validation. (a) Western blot of Pfeiffer and GM084 cell lines either expressing empty vector (EV) or eif4e, probed for BTK, YY, CDK6, total eif4e and GAPDH. (b) Western blot of SUDHL- (ABC-DLBCL) cell line treated with non-target (NT) or eif4e shrna for 48 hrs, probed for BTK, YY, CDK6, total eif4e and GAPDH. All blots shown are representative of at least three experimental replicates.

10 Supplemental Figure 0 Figure b MNK(55kD) MNK(55kD) GAPDH(36kD) Figure h Total eif4e(5kd) p-eif4e(5kd) MNK(55kD) MNK(55kD) GAPDH(36kD) Figure g Total eif4e(5kd) p-eif4e(5kd) MNK(55kD) MNK(55kD) GAPDH(36kD)

11 Figure a p-eif4e(5kd) ERK(44/4kD) Total-eIF4E(5kD) p-erk(44/4kd) p-erk long exposure(44/4kd) GAPDH(36kD) Figure b p-eif4e(5kd) Total eif4e(5kd) p-mnk/(55kd) MNK(55kD) HLY- Pfeiffer GM084 MNK(55kD) GAPDH(36kD) Figure c p-eif4e(5kd) HLY- GM084 Pfeiffer Total-eIF4E(5kD) HLY- GM084 Pfeiffer MCL-(40kD) GAPDH(36kD) HLY- GM084 Pfeiffer HLY- GM084 Pfeiffer

12 Figure h p-eif4e(5kd) Total-eIF4E(5kD) MCL-(40kD) GAPDH(36kD) Figure 3a p-eif4e(5kd) MNK(55kD) MCL-(40kD) Total eif4e(5kd) eif4e3(4kd) GAPDH(36kD) Figure 3f p-eif4e(5kd) MNK(55kD) MCL-(40kD) Total-eIF4E(5kD) eif4e3(4kd) GAPDH(36kd) Figure 3k p-eif4e(5kd) and GAPDH(36kD) MNK(55kD) MNK(55kD) Total eif4e

13 Figure 3i p-eif4e(5kd) Total eif4e(5kd) MNK(55kD) MNK(55kD) GAPDH(36kD) Figure 3n Total-eIF4E(5kD) GAPDH(36kD) Figure 3m MNK(55kD) MNK(55kD) Total eif4e(5kd) Total eif4e(5kd) GAPDH(36kD) GAPDH(36kD) GM084 Pfeiffer Jurkat HCT6

14 Figure 4a p-eif4e(5kd) Total eif4e(5kd) MCL-(40kD) eif4e3(4kd) GAPDH(36kD) HLY- Pfeiffer p-eif4e(5kd) Total eif4e(5kd) MCL-(40kD) eif4e3(4kd) GAPDH(36kD) Figure 4d Figure 4g Total eif4e(5kd) Total eif4e(5kd) eif4e3(4kd) 7 hrs 48 hrs GAPDH(36kD) Short Exposure Long Exposure

15 Figure 5a p-eif4e(5kd) Total-eIF4E(5kD) eif4e3(4kd) GAPDH(36kD) Figure 5d Figure 5f Total eif4e(5kd) Total eif4e(5kd) eif4e3(4kd) Cap-PD eif4g-ip Cap-PD Figure 5h Figure 5i eif4a(48kd) eif4g(40kd) Total eif4e(5kd) Total eif4e(5kd) short exposure eif4e3(4kd) eif4e3-ip eif4e3-ip eif4g-ip eif4g-ip Cap-PD

16 Figure 5l eif4e3(4kd) eif4e3(4kd) Empty vector vs. eif4e3 FL eif4e(5kd) eif4e(5kd) eif4e3(4kd) eif4e3(4kd) Vehicle vs. CGP57380 eif4e(5kd) eif4e(5kd) Figure 6g c-myc(60kd) Dicer(0kD) N-Myc(6kD) GAPDH(36kD)

17 Figure 6h Empty vector and eif4e GAPDH(36kD) YY(63kD) CDK6(40kD) BTK(73kD) eif4e(5kd) Figure 6h Non-target and eif4e shrna Total eif4e(5kd) GAPDH(36kD) YY(63kD) CDK6(40kD) BTK(73kD) Sup.Fig.0. Full immunoblots of segments shown in the main figures

18 Supplemental Table Data mining from oncomine ( showing the distribution of MNKs in DLBCL MNK GCB/ABC classified? MNK GCB/ABC classified? Range of Expression Range of Expression Sample Number Sample Number *Increase/decrease or split *Increase/decrease or split Source No Up fold 66 Increase Hummel et al, NEJM, 006 No Up-+fold 7 Increase Salaverria et al, Blood, 0 No Up 6+fold 40 Increase Booman et al, J Pathol 008/0/0 Yes Up 5+ fold 44 Increase Lenz et al, NEJM, 008 No Up.5+ fold 5 Increase Dave et al, NEJM, 006 No Up.5-5+ fold 84 Increase Zhang et al, PNAS 03 Yes Up 4+ fold 73 Increase Compagno et al, 009, Nature *Increase or decrease denotes the trend of fold change in MNK expression in comparison to normal tissue controls. The term split observation represents a study where some samples exhibited an increase while others exhibited a decrease. Source No -8 to +3 fold 58 Split Shipp et al, Nature Med, 00 Yes -5 to +0.5 fold 44 Decrease Lenz et al, NEJM, 008 No About + fold 4 Increase Klapper et al, Blood, 008 No -0.5 to +0.5 fold Split Brune et al, J Exp Med 008 Yes -4.5 to + fold 69 Decrease Shaknovich et al, Blood 00 No -0.5 to +0.5 fold 3 Split Lossos et al, PNAS, 00 *Increase or decrease denotes the trend of fold change in MNK expression in comparison to normal tissue controls. The term split observation represents a study where some samples exhibited an increase while others exhibited a decrease.

19 Supplemental Table eif4e and eif4e3 translatome a: The list of significantly altered genes in eif4e translatome Symbol (Z-ratio) ETL- ETR (Z-ratio) E3TL- E3TR ALD ABHD ABHD ABL ACOT ADAM ADD ADORAA.84.4 ADRBK.07.4 ALG ALKBH ALKBH AMFR ANKMY..4 ANKRD ANXA.5.3 AP3S.8.3 APHA APHA ASB ASB ASCC ASNA ATF ATG9A ATP5G ATP6VG.80.8 AXUD.65.4 BAK.57.6 BCLL BCLL BCLL.0.4 BLOCS.89.4 BOLA.09.3 BRP Corf Corf Corf73..9 Corf C6orf C7orf C7orf C7orf C7orf C7orf C8orf C9orf8.09. C9orf C9orf Corf Corf Corf Corf Corf C0orf Corf Corf Corf Corf C3orf C5orf3.33. C5orf C6orf C6orf C7orf.3.6 C9orf C9orf C9orf C9orf C9orf C9orf CARD CARKD CCDC0 A CCDC CCDC CD63L.65.4

20 CD99L.08.5 CECR CENPM CENPV CENPV.46.4 CHCHD6.9.0 CHIC CHMPA CINP.8.03 CLCN CMTM COQ CRADD.76.0 CRTC CSNKD.00. CSNKD CSNKG CUTA.86.4 CUTA CXorf40A.4.76 CXorf40A CXorf40B.8.49 CYHR DAP.57.3 DCTD DCTD.7.48 DCTN DDA.89.9 DDX.07.3 DENNDA DENNDA DEXI DGCR DGCR DHDH.73.7 DLEU.6.37 DNASEL DNPEP DPH DPM DRAP DTD DTX.96.3 DVL EBP ECE ECGF ECSIT EEFB EEFB.68.3 EFNA EI EMD EML ENDOG ENSA..5 ENTPD ERGIC ESRRA EVI5L EXTL F8A FAHDB FAM6B FAM5A FAM8A FAM34A FAM4B.7.8 FAM60A FAM64C FAM89B FAM3A.7.45 FAM54B FAM58A.8.3 FAM86A FAM86B.56.0 FANCA FAT FBXO8.6.3 FBXW FGGY FGGY FLCN.93.4 FLJ FLJ FLJ GBA GCHFR

21 GLRX.9.4 GMFG.9.5 GMPPB GNG GPBAR GPR GPR GRB GSTZ HFX.9.0 HAFX HAGH HAGHL HAX HDDC.8.4 HIGDA.67.8 HINT HISTHA C HISTHB G.73.4 HISTHB J HISTHB K.69.8 HISTH4J.5.50 HISTHA A HISTH3A HISTH3C HIST3HA HMG0B.43.8 HN.73.6 HPCAL HSPC IFI7L IFI IL0RB IMMPL.84.4 IQSEC IRAKBP ISOC ITFG KCTD KDELR.5.38 KIAA KRT LAT.70.8 LCMT LLGL.47.4 LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC

22 LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LONP.55. LPCAT LRCH LRRC0.3.0 LY6E LYPLA LYSMD MADL MAF MAP4K MAP6D MAPK MCOLN MED MED MESP.6.3 MFN.55.3 MGAT4B MGC MIF4GD.86.5 MKNK MOBKLC MONB MRPL MRPL MRPS.5.43 MRPS MSI MTP MYO

23 MYST NACC.6.48 NARF.97.5 NAT NCKIPSD.4.33 NDE NDST.4.6 NHPL NICN.5.4 NKIRAS.57.9 NLRX.6.03 NME.05. NME- NME.64.8 NME NOTCHN L NUDT OBFC OPA ORC6L ORMDL OSCP.9.37 PAGE PAGEB.6.08 PAOX PARD6A PARVB.5.7 PDE6D PDF PDXK PEA PEX PEX PFKFB PGAM PGAM PGAP PHF PIM PIN.99.9 PLAGL PLAUR.54.9 PLAUR PLD PLSCR PMM POLRC POLRJ.8.45 POMGNT.70.4 PPCS.0.7 PPPRB PRRG PRSS PSD4.3.7 PSENEN PSMA PSMB PSMD3.80. PTRH PYCR RABFIP RABB.56.9 RAB33A RAB40C RAB5C RAB5C.50.0 RBM RDH RER REXO RFC.76.6 RHOC RNF RNF RNF RNF RNF RNF5P.0.45 RP- 59I RPESP RPL RPRC RPS6KB.38.0 S00A SCAMP SDHALP SFXN

24 SFXN SH3GLB SIDT SIGMAR.68.0 SIPA.0.6 SLC0A SLC0A SLC5A SLC5A SLC5A SLC5A SLC39A.8.49 SLC39A4.3.9 SLC48A.8.45 SLC7A SMPD SNAPC SNAPC SNRPN SORT SPNS SPRYD SPSB SPTLC SRI.90.3 SRP SSR ST3GAL ST6GALN AC ST6GALN AC ST8SIA ST8SIA STK STK STX STX SYTL TAPBP TEAD TFAMP.79.0 THOC TIMM TMC TMED9.6.0 TMEM TMEM TMEM TMEM85 A.7.8 TMEM TMEM TMEM4A TMEM55B TMEM TMEM TMEM TMPRSS TMUB TNFRSF TNIP TOML.6.8 TP53I TPI.78.6 TPRGL TRAPPC6 A.08.7 TRMT.7.30 TRPT TSPAN TSPAN TSTD.56.4 TYK.65.4 UBED UBEM UNC UPLP.9.43 UPP..48 UROS.59.0 USMG VEGFB VEGFB WBP WBSCR WDR WDR WIBG YIFB YIPF

25 YIPF ZBTB ZDHHC8..0 ZDHHC ZFYVE ZMYM ZNF ZNF ZNF ZNF ZNF ZNF ZNF ZNHIT ZSCAN5A.67.0 b. The list of significantly altered genes in eif4e3 translatome Symbol (Z-ratio) ETL-ETR (Z-ratio) E3TL-E3TR ACOT ADCK.49.8 ADPGK ADRM ADRM.5.39 AEN.8.83 ALG ALKBH.08.7 ARL6IP ASFB ASRGL ATP5J.9.57 ATP5J.4.6 ATP5J.5.57 BANF BCSL BIRC5.5.5 BRI3BP BSDC.5.50 BUB C5orf C6orf C6orf C7orf53..9 C8orf C9orf C9orf C9orf Corf Corf C7orf C9orf40..9 CALM CAMKG CASP.3.86 CASP CBR..60 CCDC CCDC CCL3L CCNE..70 CCRN4L CDC CDC5A CDC5B CDC CDK CDK5R CDS.3.75 CDT CEBPA CENPN CFL CHAFA CHPF.8.76 CIAPIN..67 CIDEB..54 CKLF.4.04 CKLF CLDN CLN CMTM

26 CNIH CNIH..7 COMMD COX6C.0.5 CSFRA.9.53 CTSB.4.6 CXorf CXXC.7.4 DDOST.6.55 DDRGK.6.7 DDX DDX5.0.9 DENND4B DHRS 0.9. DHRS.06.9 DOLPP DOTL DPP DUS3L DUSP EBNABP EEFB.6.8 EIF3I ERAL.0.58 ERCC.8.55 EXOSC FABP FARS FAU FBL FBXO FEN FHOD FKBPL FLAD.5.59 FLJ FLJ FTSJ GAGEC..9 GAGEE.8.75 GAGEH.4.74 GAGEB.0.6 GAGE GINS GMIP.4.58 GORASP GTF3C H3F3A.0.0 H3F3A.0.7 HAUS HAUS HAUS HISTHAH HISTHBE HISTH4C HNRNPAB HRASLS.37.4 HSHD.0.5 HSPE HTRA HYAL.3.66 ID ID IGLL IKBKE.8.07 IL IQCC.4.6 IRAK ITGAE.6.8 ITMC ITMC KIAA KSR KTI LDLRAP LMAN LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC

27 LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LOC LRRC LRRC LRWD.44.8 LSM LSM LSM5.4.6 Magmas.6.55 MCAT.3.54 MCM MDH.6.76 METTD MLLT MRI MRPL MRPL MRPL MTX NDUFB NFKBIA NFKBIL NOL NPM NRF.3.75 NTHL.48.9 NUBP.4.0 NUBP NUDC.7.4 NUDCD ODC PARL PARP.09.6 PATE PCNA PEXB.0.5 PFDN PFN PIGU.45.7 PKMYT.7.94 PLD POLA POLRC POLRC POUAF PPAN-PRY PPPR PPT PRCC PRDX PRDX PRDX5.4.6 PRPF PRPF38A PRR PRR PRR PSMA PSMB PSMB4.3.4 PSMB PSMB PSMB PSMD3.5.7

28 PSME PSME PSME3..53 PTTG PTTG3P PUS.6.6 PUSL.9.97 PXMP.8.64 RAD5L RAD54L.0.84 RAD9A.06.7 RAN.50.5 RASSF RASSF RBM RDH RECQL4.4.8 RNASEHC.0.64 RNPS.8.68 RPA RPL0A RPP RPS5A RPS6L RPS6L.4.3 RPS7L.08.6 RPS7L.9.04 RPS6KA RPS RRP RSAD SAMD.6.79 SAPS SCARNA SCLY SEC6G SFRS SFRS SFXN.9.84 SHD3A SH3RF.9.58 SIGMAR.4.75 SIGMAR SLC5A4.3.5 SLC9A SLC9A.7.86 SLC38A SLC38A SLC39A SNHG SNRPB SNRPD.3.99 SNRPF.4.53 SOD.4.53 SPC SPCS.40.9 SSBP..84 ST3GAL STMN SUV39H.44.3 SYK TBCA.4.7 THL.3.70 THL.7.96 THOC THOC5..87 TM9SF.0.55 TMSB4X.5.79 TNFRSF8..67 TOMM TOMM7.9.9 TPM TPST.3.56 TRAF..54 TRIM TRIM TRIP TRIP TRMT6A TSFM.39.3 TTC TTC TUBA3C TUBA3D TUBG TXN.9.30 TXNDC TYMS 0.8.3

29 UAF UBA UBXN UCHL5IP UCHL5IP UFDL.4.57 UNG VCX VCX-C VCX3A VISA VPS WDR WWOX ZCCHC ZNF ZNF

30 Supplemental Table 3 eif4e candidate motif targets #Ensembl.ID Motif ID Entrez Gene ID Gene Name Chromosome ID Gene Set ENSG KDELR 7 Target 56(-) ENSG MRPS 9 Target 54(+) ENSG CIAPIN 6 Bg 37(+) ENSG COQ9 6 Target 47(-) ENSG NKAIN 6 Bg 6(-) ENSG RARB 3 Bg 9(-) ENSG PDE6D Target 3(-) ENSG DTD 0 Target 5(-) ENSG AMFR 6 Target 3(-) ENSG TSPAN3 Target 53(-) ENSG CETN X Bg 8(+) ENSG NDST 0 Target 93(+) ENSG MCOLN 9 Target (+) ENSG MKNK 9 Target 97(-) ENSG PRCP Bg 39(-) ENSG ID Bg 79(-) ENSG SLC38A Bg 5(-) ENSG COMMD8 4 Bg 39(+) ENSG POUAF Bg 58(-) ENSG LCMT 6 Target 6(-) ENSG TMED9 5 Target 9(-) ENSG MLF Bg 9(+) ENSG PSMA7 0 Target (+) ENSG B3GALNT Bg 97(+) ENSG IFT5 0 Bg 87(-) ENSG FAM89B Bg 98(-) ENSG RCC Bg 56(-) ENSG ISOC 9 Target (-) ENSG HIC 7 Bg 48(+) ENSG TOP3A 7 Bg 0(+) ENSG ATG 5 Bg 7(+) ENSG TMEM89 0 Target 4(-) ENSG PLD3 9 Target 73(-) ENSG PPPR3C 4 Bg 3(-) ENSG ZNF548 9 Bg 85(+) ENSG MRPL6 Bg 5(+) ENSG TP53RK 0 Bg 77(+) Motif Position (s)

31 ENSG HIGDA 5 Target 40(-) ENSG CCBL Bg 48(+) ENSG PLCG 6 Bg 85(+) ENSG GCHFR 5 Target 85(-) ENSG NOP6 5 Bg 8(+) ENSG KIAA Bg 63(+) ENSG IFITM Bg 3(-) ENSG POLA X Bg 6(+) ENSG CRADD Target 4(+) ENSG DGCR6 Target 89(+) ENSG DCLREB Bg 50(-) ENSG NOS 7 Bg 8(-) ENSG ZNF749 9 Bg 78(+) ENSG RPL39L 3 Bg 33(+) ENSG CSNKG 9 Target 8(-) ENSG FAM53A 4 Bg 89(-) ENSG SIDT Target (+) ENSG MRPL0 Target 7(+) ENSG INCENP Bg 87(-) ENSG VPS37B Bg 80(-) ENSG CDK Bg (-) ENSG GNG5 Target 9(+) ENSG PRRC 5 Bg 05(-) ENSG CCDC06 9 Target (+) ENSG IQSEC3 Target 43(+) ENSG PSMC3 Bg 4(+) ENSG TOML 7 Target (+) ENSG ANKMY Target 8(+) ENSG MTMR X Bg (-) ENSG ZNF655 7 Bg 7(+) ENSG BTK X Bg (+) ENSG GDPD5 Bg 43(+) ENSG DNAJB 0 Bg 0(-) ENSG KIAA79 0 Bg 57(-) ENSG MINPP 0 Bg 3(-) ENSG ZNF40 4 Target (+) ENSG GSPT 6 Bg 3(+) ENSG ANKRD6 0 Target 37(-) ENSG IFI7L 4 Target 8(-) ENSG CLCN7 6 Target 88(+) ENSG CNOT7 8 Bg 3(+)

32 ENSG AP3S 5 Target 63(-) ENSG ZCRB Bg 6(+) ENSG THOC6 6 Bg 48(+) ENSG ZBTB45 9 Target 68(+) ENSG TESC Bg 8(-) ENSG GTSE Bg 50(-) ENSG TYK 9 Target 7(+) ENSG HCFCR 6 Bg 44(-) ENSG TTC37 5 Bg 04(+) ENSG SLC39A Target 4(-) ENSG FOXO4 X Bg 33(+) ENSG PMM Target 5(+) ENSG PLIN 9 Bg 6(+) ENSG MRPS 9 Bg 33(+)

33 Supplementary Table 4 eif4e3 candidate motif targets #Ensembl.ID Motif ID Entrez Gene ID Gene Name Chromoso me ID Gene Set Motif Position (s) ENSG PRPF9 Target 75(-) ENSG ZNHIT6 Bg 6(+) ENSG COX7 3 Bg 79(-) ENSG LIG3 7 Bg 45(+) ENSG CPSF 8 Bg 68(+) ENSG SUMO 7 Bg 60(-) ENSG DMC Bg 96(-) RP- ENSG P7.4 X Bg 58(-) ENSG YWHAE 7 Bg 90(+) ENSG ECT 3 Bg 40(+) ENSG ZNF653 9 Bg 0(-) ENSG SPATSL Bg 58(-) ENSG DUSP8 Bg 9(+) ENSG MCM8 0 Bg 7(+) ENSG PGRMC X Bg 8(+) ENSG ZNF564 9 Bg 07(-) ENSG CEP78 9 Bg 5(+) ENSG IQCC Target 0(-) ENSG PCM 8 Bg 8(-) ENSG MTERFD3 Bg 3(-) ENSG TFDP 3 Bg 8(+) ENSG RANBP Bg 9(+) ENSG ZNF770 5 Bg 84(+) ENSG WWOX 6 Target (-) ENSG AGPS Bg 6(+) ENSG POLA Target 75(-) ENSG ETFA 5 Bg (+) ENSG CPT Bg 89(+) ENSG PGPEP 9 Bg 7(+) ENSG DNAJC4 Bg 80(+) ENSG WBSCR 7 Bg 5(+) ENSG AXIN 7 Bg 7(-) ENSG PFDN5 Target 75(-) ENSG NUP55 5 Bg 95(-) ENSG KHSRP 9 Bg 6(-) ENSG SCO Bg 3(-)

34 ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG DDX8 Bg 93(-) 7374 UNG Target 9(+) 8793 TNFRSF0D 8 Bg 6(-) 7386 UQCRFS 9 Bg 9(-) 08 RBM5 3 Bg 4(-) 098 ESD 3 Bg 39(-) 6494 SIPA Bg 8(+) 508 MRPS7 7 Bg 65(-) 6597 SMARCA4 9 Bg 54(-) 38 HNRNPAB 5 Target 07(-) 683 SUPV3L 0 Bg 3(+) 8805 TRIM4 7 Bg 3(+) 9985 SLC39A3 9 Target 0(+) AVPI 0 Bg 3(-) 9988 DMTF 7 Bg 43(-) 9088 PKMYT 6 Target 7(-) 55 PPPR8 Target 3(+) 68 RPA Target 4(-) 7903 PDCL3 Bg 6(-) 0576 CCT Bg 3(+) 9409 CCDC74B Bg 9(+) 043 CDIPT 6 Bg 4(+) 795 TXN 9 Target 4(-) 44 MANA 5 Bg 09(-) 5539 ANKZF Bg 39(-) 378 ARF4 3 Bg 60(+) 7343 POLL 0 Bg 4(+) 5708 TRMT6A 4 Target 47(-) 395 STMN Target 8(-) 0989 IMMT Bg 63(+) 638 KLHDC3 6 Bg 63(-) 3087 AHSA Bg 79(-) 5589 MYNN 3 Bg 6(+) 6636 SNRPF Target 6(-) 749 HTRA Target 7(-) 4580 MTX Target 79(+) TOMM7 7 Target 54(+) 574 PSMD8 9 Bg 55(+) FGD6 Bg 74(-) 045 TIMM7B X Bg 30(+) PANK3 5 Bg 46(-)

35 ENSG RCC Bg 4(+) ENSG APBBIP 0 Bg 70(+) ENSG SERTAD3 9 Bg 7(+) ENSG CNBP 3 Bg 38(-) ENSG TTC37 5 Bg 66(+) ENSG TYMS 8 Target 45(+) 73(+) ENSG STIM 4 Bg 37(-) ENSG SEPSECS 4 Bg 5(-) ENSG YIPF6 X Bg 64(+) ENSG SEPW 9 Bg 64(-) ENSG M6PR Bg 7(-) ENSG USP33 Bg 54(-) ENSG ALG4 Target 6(+) ENSG GAGEE X Target 5(+) ENSG BRI3 7 Bg (-) ENSG FOXN3 4 Bg 46(-) ENSG PUS Target 04(+) ENSG ILVBL 9 Bg 4(-) ENSG ANKRD35 Bg 0(+) ENSG GALT 9 Bg 5(-) ENSG UBET Bg 5(+) ENSG AKR7A3 Bg 77(-) ENSG SPR4 9 Bg 7(+) ENSG PTTG 5 Target 3(+) ENSG SUV39H X Target 63(+) ENSG GAGEA X Bg 6(+) ENSG SLCO4C 5 Bg 7(+) ENSG SYK 9 Target 64(+) ENSG REV3L 6 Bg 79(+) ENSG CD83 6 Bg 59(-) ENSG HES 3 Bg 37(-) ENSG FAM0A 0 Bg 59(-) ENSG RARB 3 Bg 77(-) ENSG CENPM Bg 69(+) ENSG PFKFB4 3 Bg 47(+) ENSG UCK Bg 9(-) ENSG SNRPD 9 Target 74(+) ENSG ERCC 9 Target 0(+) ENSG GAGEC X Target 5(+) ENSG IPO 5 Bg 9(-) 54(-) ENSG TBCDA Bg 76(-)

36 ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG IMPAD 8 Bg 8(-) LYAR 4 Bg 6(+) 34 IDI 0 Bg 0(-) 69 TCEB 8 Bg 7(-) 3649 POLA Target 90(+) 70 TMF 3 Bg 09(-) 4850 CNOT4 7 Bg (-) 9538 EI4 Bg 39(+) 556 NAT0 Bg 68(-) 535 IRAK4 Bg 7(+) 433 MET 7 Bg 3(+) 3347 SMCHD 8 Bg (+) 98 VAPA 8 Bg 3(+) 6535 TIMM3B 0 Bg 7(-) 00(-) AURKAIP Bg 4(+) BOLA 6 Bg (-) RP- - 95F9.9 9 Bg 43(-) INTS 7 Bg 60(+) 7444 VRK Bg 60(+) - GAGEH X Target 5(+) 38 HNRNPAB 5 Target 66(+) 95 EEFA 6 Bg 30(+) 578 GAGE X Bg 54(+) 9985 SLC39A3 9 Target 4(-) 0548 TM9SF 4 Target 56(+) 66 POLR3D 8 Bg 55(+) 9088 PKMYT 6 Target 74(-) - SHB 7 Bg 9(-) ZNF63 9 Bg 84(+) 993 CDC5A 3 Target 85(-) 5543 CDCA8 Bg 83(+) - GAGED X Bg 5(+) 643 MLST8 6 Bg 40(-) 3480 SEC6G 7 Target 56(+) 5897 RNF9A 8 Bg 5(-) FBXL 9 Bg 79(+) DDX49 9 Target (-) CLK4 5 Bg 49(+) 530 PHF0 0 Bg 4(+) 405 MEFA 5 Bg 96(-) ATG9A Bg 58(-)

37 ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG ENSG WDR55 5 Bg 8(+) 74 TMSB4X X Target 7(+) 9588 PRDX6 Bg 8(-) - GAGEJ X Bg 39(+) 55 LRRC0 0 Bg 7(-) 578 BAK 6 Bg 87(-) 4087 SMAD 8 Bg 55(-) 67 SRF 6 Bg 4(+) GAGEG X Bg 5(+) 79 ZNF77 7 Bg 4(+) 59 PEX0 Bg 8(-) - TOPA 7 Bg 00(+) HOOK3 8 Bg 33(-) 545 WDR44 X Bg 64(-) 646 TFBM Bg 5(+) MTA3 Bg (-) 9404 SESTD Bg 60(-) 7697 ZNF38 7 Bg 6(-) 663 SNRPC 6 Bg 54(+) DHRS 3 Bg 69(+) DCAF6 4 Bg 8(+) 79 GCLC 6 Bg 57(+) 55 PHF 6 Bg 34(-) 90 SOCS3 7 Bg 7(+) GXYLT Bg 30(+) 577 DNAJC7 Bg 65(+) 909 PIGQ 6 Bg 4(-) 5486 GIN 5 Bg 9(+) - GAGEF X Bg 5(+) 9766 TMOD3 5 Bg 3(-) 759 TSPYL 6 Bg 5(+) LRRC45 7 Target 5(+)

38 Supplementary Table 5 Nucleotide frequency table indicating the rate of nucleotide occurrence in each position of a motif eif4e Motif A C G T Motif A C G T eif4e3 Motif A C G T Motif A C G T

39 Supplementary Table 6 Comparison of eif4e and eif4e3-driven 5 UTR motifs to TOP motif a. Nucleotide frequency table of the TOP motif (Thoreen et al, 0 and Eliseeva et al 03). Motif A C G T b. Divergence scores for each motif (with and without reverse complementing) when compared to the TOP motif Raw divergence value eif4e eif4e3 Motif Motif Motif Motif Motif TOP- like motif sub- sequences Direction same opposite same opposite same opposite same opposite Minimum divergence value eif4e eif4e3 Motif TOP motif Divergence Score Direction TOP motif sub- sequence Motif opposite Motif same 3.. Motif same Motif 0.7 same.. 0

40 Supplementary Table 7 a) shrna sequences shrna target (catalog number) MNK (TRCN ) MNK (TRCN ) MNK (TRCN ) eif4e (TRCN ) eif4e3 (TRCN ) eif4e3 (TRCN ) eif4e3 (TRCN ) eif4e3 (TRCN ) Sequences CCGGTGCTCCAGTCACACCTTATAGCTCGA GCTATAAGGTGTGACTGGAGC CCGGCCTAGAGCTGATTGAGTTCTTCTCGA GAAGAACTCAATCAGCTCTAGGTTTTT CCGGCATGTGTTAATGTTACGATGTCTCGA GACATCGTAACATTAACACATGTTTTTG CCGGCGGCTGATCTCCAAGTTTGATCTCGA GATCAAACTTGGAGATCAGCCGTTTTTG CCGGCCATGAAGAGCATCATGCTTTCTCGA GAAAGCATGATGCTCTTCATGGTTTTTTG CCGGCCAATAGGAAACCTGATGTTTCTCGA GAAACATCAGGTTTCCTATTGGTTTTTTG CCGGGCAGCAGATGATGAAGTAATACTCG AGTATTACTTCATCATCTGCTGCTTTTTTG CCGGGTTTGGAAAGAGTTGCTGTTACTCGA GTAACAGCAACTCTTTCCAAACTTTTTTG b) Primer sequences used in RT-qPCR analyses Target Gene GAPDH MNK MNK eif4e DTD DGCR6 FLCN Bub3 LSM4 FAU Primers For- CGGAGTCAACGGATTTGGTCGTA, Rev-AGCCTTCTCCATGGTGGTGAAGAC For-TGCTTTTGCTTCTGGATGT Rev-AGAAACAAGCAGGGCACAGT For-AGTCCCCGTTGAGTTTGAT Rev-AAAGCCGGAAAACATCCTCT For-AGTGACCTCGATCGCTTTTG Rev- ACATTAACAACAGCGCCACA For-TGAGGATGAGAGTGGGAAGC Rev-GCTCCGGCCTGTATGTTTTA For- GCTGCCTTTCTGGTCACACT Rev- CAGCAGAGCACACTGGAGAA For- CCAGCTCTTCAGCATTGTCC Rev- GAGGTAGATCCGGTCCATCA For-AATGCTGGGACCTTCTCTCA Rev-GGCTTGGGTCCAAATACTCA For- GATGCCCGAGTGCTACATC Rev- CTGTCTGCCAGGCTTCTTCT For- CCCAGGAGCTACACACCTTC Rev- TTGGCCACCTTAGGAGTCTG