Definizione Linfomi
• Espansione clonale di una cellula linfoide
bloccata ad un determinato stadio di
maturazione
• Localizzazione linfonodale,
emato-midollari, extra-linfonodale
A NTIG ENE CELLULA STAMINALE LINFOIDE
Cellula pre-B Cellula naive
SANGUE LINFONODO Cellula mantellare
Centroblasto
Blasto follicolare centrocicto
Linfocito z. marginale
plasmacellula
Sede infezione Midollo
Origine cellulare e patogenesi molecolare dei LNH
Ricombinazione Ig porzioni VDJ sIg M ID OL L O OSSEO EM OPOI ET IC O
rearrangement 3’ 3’ 5’ 5’ V D J Cμ
Heavy Chain Gene – 14q32
Constant region Heavy Chain Light Chain
G, A, E, D
Long-lived plasma cell
Pre-B cell IgM Short-lived plasma cells Germinal centre Cell precursor Plasmablast GERMINAL CENTRE MEMORY B-CELL
Bone Marrow
Lymph node
VDJ
rearrangement
Ig gene rearrangements (in the lymph node germinal centre)Folli
colo
li
nfonod
ale
Zona basale scura
Z ona apic ale c hiara Z ona bas ale c hiara
MANTELLO FOLLICOLARE
blasti B primari centroblasti Incontro con Ag Ipermutazione somatica IgHV Switch Ig centrocito Bassa affinità apoptosi Elevata affinità per l’Ag Sopravvivenza BCL2+ BCL2- Cellula memoria Plasmablasto Plasmacellula BCL6- BCL6-CENTR
O
GERMINA
TIV
O
BCL2- BCL6+Formazione del centro germinativo
Epigenetic remodelling
Chromosomal translocations leading to
proto-oncogene deregulation
C R C RPartner gene
proto-oncogene
C RTranscriptional deregulation
of proto-oncogene
CHROMOSOMAL TRANSLOCATION
RFusion transcript &
chimeric protein
C
Consequences of chromosomal translocations
leading to transcriptional deregulation of proto-oncogenes
C R
NORMAL GENOME (DNA)
C R C R C R C R C R
NORMAL TISSUE
(mRNA & PROTEIN)
R
LYMPHOMA GENOME (DNA)
C
TF
TF
TF TF
The translocation has caused the jusxtaposition of the
regulatory regions of the blue gene in the proximity of the red gene. Expression of the red gene is now directed by the
regulatory regions of the blue gene!
LYMPHOMA TISSUE
(mRNA & PROTEIN)
ALCUNE TRASLOCAZIONI PRIMARIE
IMPORTANTI NELLA PATOGENESI DEI LINFOMI
IgH locus Partner di traslocazione 11q13 CICLINA D1 18q21 BCL2 8q24 C-MYC
EFFETTO
sopravvivenzaCRESCITA
Cromosoma 14 3q22 BCL6 Crescita Crescita / controllo trascrizioneGerminal centre Follicle mantle
Mantle cell
lymphoma
t(11;14) BCL1/CCND1 Marginal zone lymphoma Large cell Lymphoma (DLBCL) Follicular lymphoma t(14;18) BCL2 t(3;V) BCL6Memory
B-cells
Burkitt’s lymphoma t(8;14) Myc Lymphoplasmacytic lymphoma t(9;14) PAX5 17p-/p53 del 17p-Folli
colo
li
nfonod
ale
Zona basale scura
Z ona apic ale c hiara Z ona bas ale c hiara
MANTELLO FOLLICOLARE
blasti B primari centroblasti Incontro con Ag Ipermutazione somatica IgHV Switch Ig centrocito Bassa affinità apoptosi Elevata affinità per l’Ag Sopravvivenza BCL2+ BCL2- Cellula memoria Plasmablasto Plasmacellula BCL6- BCL6-CENTR
O
GERMINA
TIV
O
BCL2- BCL6+Formazione del centro germinativo
Epigenetic remodelling
The t(14;18)(q32;q21) translocation of FL involves
IGH on chr. 14q32 and BCL2 on chr. 18q21
t(14;18) leads to transcriptional deregulation of BCL2, which
in turn shifts the apoptosis balance toward survival
t(14;18) translocation is insufficient for FL development
t(14;18) is insufficient for the development of FL
90% of FL have the t(14;18)
Over-expression of anti-apoptotic BCL2
Transgenic mice do not develop FL
(McDonnell et al., 1989; McDonnell et al., 1991)
Healthy individuals carry the translocation
(Limpens et al., 1995, Dolken et al., 1996; Summers et al., 2001; Roulland et al, 2006)An epigenetic ‘addiction’ in FL
90% of cases had at least one mutation in an epigenetic regulator
SOX11: promotes tumor angiogenesis and cross-talk between MCL cells and microenvironment SOX1 silencing in a MCL xenograft
Linfomi MALT
• Eziologia infettiva:
HP
C. Jejuni – immunoproliferative small intestinal disease
B. burgdoferi – MALToma cutaneo
C. psittaci – linfoma MALT orbitario
HCV – linfoma della zona marginale splenico
• Eziologia autoimmune:
Tiroidite di Hashimoto – linfoma marginale tiroideo
In condizioni fisiologiche lo
stomaco
NON
possiede
tessuto linfoide associato
alle mucose (MALT)
infiammazione cronica da H. pylori
linfocita TH H. pylori specifico (Ureasi, CagA, VacA, HSP)
CD40 CD40L MCH II - ATG TCR linfocita B Proliferazione ed organizzazione di follicoli linfatici
Neo – MALT
Linfociti CD8: controllo sulla proliferazione BIn condizioni fisiologiche lo
stomaco
NON
possiede
tessuto linfoide associato
alle mucose (MALT)
infiammazione cronica da H. pylori
linfocita TH H. pylori specifico (Ureasi, CagA, VacA, HSP)
CD40 CD40L MCH II - ATG TCR linfocita B Proliferazione ed organizzazione di follicoli linfatici
Neo – MALT
Linfociti CD8 Viene meno il controllo sulla proliferazione B Flogosi Neutrofili attivati (?) ROS (?) Danno geneticoPrincipali alterazioni Citogenetico-molecolari
t (11;18)(q21;q21)
API2-MALT1
t (14;18)(q32;q21)
IGH-MALT1
t(1;14)(p22;q32)
IGH-BCL10
t(3;14)(p13;q32)
IGH-FOXP1
Genetic pathways leading to MALT NHL
HP+
Chronic inflammation
Others (?)
translocations
aneuploidy
Up-regulation of
specific genes
Gene dosage
effect
Significance of translocations
API2-MALT1
IGH-MALT1
IGH-BCL10
API2-MALT1 fusion protein MALT1 under control of IgH promoter BCL10 under control of IgH promoter
Role of chronic inflamation and translocations in the pathogenesis of MALT NHL
Chronic inflamation bacteria (HP) – self antigen
T-B interaction PROLIFERATION (appearance of MALT in the stomach) MALT1 activation Increased BCL10/MALT1 complex Increased NFkB APOPTOSIS IgH/MALT1 translocation API2/MALT1 Translocation (stable protein) BCL10 Translocation
MALT lymphoma HP-dependent: eradication is effective
Unknown genetic events (+3; others)
MALT lymphoma with translocations HP eradication is ineffective
Increased NFkB
IgH/MALT1
Gastric MALT NHL
Low grade gastric MALT NHL is usually caused by HP infection. It is an indolent disease but may become locally
aggressive, spread, or undergo high grade transformation. Treatment of the infection cures the disease in ~70% of cases. Resistant or non-localised disease is treated with
chemoimmunotherapy (alkylating agents + Anti CD20 Mo Ab Rituximab)
