LAURA%PASQUALUCCI%(NEW%YORK)
GENETICS5DRIVEN%EPIGENETIC%DYSREGULATION%IN%LYMPHOMA:%
THERAPEUTIC%IMPLICATIONS%
! Institute(for(Cancer(Genetics,(Columbia(University,(New(York(NY(
!
Diffuse! Large! B! cell! Lymphoma! (DLBCL)! and! Follicular! Lymphoma! (FL)! represent! the! two!
most! common! forms! of! B! cell! non<Hodgkin! Lymphoma! (B<NHL),! together! accounting! for!
~60%! of! de<novo! diagnoses.! Despite! significant! progress! in! the! management! of! these!
cancers,! approximately! 30%! of! DLBCL! patients! do! not! respond! to! currently! available!
treatment!approaches,!even!after!salvage!therapies,!and!FL!remains!essentially!incurable.!A!
better! understanding! of! the! mechanisms! that! are! responsible! for! tumor! initiation! and!
maintenance! is! critical! to! improve! our! ability! to! diagnose,! prognosticate,! and! treat! these!
patients.!
Mutational! targeting! of! histone/chromatin! modification! genes,! including! the!
methyltransferase! KMT2D! and! the! acetyltransferases! CREBBP! and! EZH2,! emerged! from!
pioneering! genome! sequencing! studies! as! a! highly! frequent! somatic! event! in! both! FL! and!
DLBCL,!revealing!a!prominent!role!for!epigenetic!dysregulation!in!the!process!that!leads!to!
the! malignant! transformation! of! germinal! center! B! cells,! the! FL/DLBCL! cell! of! origin1<3.!
Mutations! of! CREBBP! and! KMT2D! inactivate! the! enzymatic! function! of! these! proteins! and!
are! acquired! early! during! the! evolutionary! history! of! the! tumor! clone,! in! a! “common!
mutated! precursor”! cell! that! subsequently! progresses! to! overt! lymphoma! through! the!
accumulation! of! additional! genetic! alterations4,5.! This! presentation! will! summarize! recent!
advances!on!the!role!of!CREBBP!and!KMT2D!in!the!normal!physiology!of!the!germinal!center!
reaction!and!the!mechanisms!by!which!genetic!loss!of!these!two!enzymes,!individually!and!in!
combination,! contributes! to! lymphomagenesis! through! the! impairment! of! terminal! B! cell!
differentiation! and! the! interaction! with! the! immune! environment6,7.! Novel! findings! on! the!
identification!of!vulnerabilities!that!are!established!by!CREBBP!mutations!in!the!lymphoma!
cells! and! their! clinical! implications! will! be! discussed8,! as! related! to! the! development! of!
improved!biomarkers!and!potentially!novel!therapeutic!principles!for!the!treatment!of!these!
lymphomas.!!
!
References:%%
1. Pasqualucci!et!al.,!Nature!2011!
2. Morin!et!al.,!Nature!2011!
3. Pasqualucci%et%al.,%Immunological%Reviews%2019%
4. Pasqualucci!et!al.,!Cell!Reports!2014!
5. Okosun!et!al.,!Nature!Genetics!2014!
6. Zhang!et!al.,!Nature!Medicine!2015!
7. Zhang!et!al.,!Cancer!Discovery!2017!
8. Meyer%et%al.,%Immunity%2019%
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SCIENTIFIC PROGRAMME
SESSION I
HODGKIN’S DISEASE
DEBATE I
IS THERE STILL A ROLE
FOR COMBINED MODALITY
THERAPY FOR EARLY
STAGE CHL?
SESSION II
T-CELL LYMPHOMA
ROUNDTABLE I
FUTURE DIRECTIONS IN
T-CELL LYMPHOMA
SESSION III
FOLLICULAR LYMPHOMA
DEBATE II
CAN WE AVOID
CHEMOTHERAPY IN
THE MANAGEMENT OF
FOLLICULAR LYMPHOMA?
SESSION IV
RARE LYMPHOMAS –
MARGINAL ZONE
LYMPHOMA AND
WALDENSTRÖM M
ACROGLOBULINEMIA
ROUNDTABLE II – WHERE
TO GO IN RARE B-CELL
LYMPHOMAS
SESSION V
MANTLE CELL LYMPHOMA
SESSION VI
DIFFUSE LARGE B-CELL
LYMPHOMA
DEBATE III
DO WE STILL NEED ASCT
IN MCL?
SESSION VII
NOVEL THER APEUTIC
CONCEPTS IN B-CELL
LYMPHOMAS
SELECTED ABSTRACTS
FOR AN ORAL
PRESENTATION
SELECTED ABSTRACTS
FOR A POSTER
PRESENTATION
DISCLOSURES