Hairy cell leukemia Prof. Arcangelo Liso Università di Foggia Rieti 27 ottobre 2006.
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Transcript of Hairy cell leukemia Prof. Arcangelo Liso Università di Foggia Rieti 27 ottobre 2006.
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Hairy cell leukemia
Prof. Arcangelo Liso
Università di Foggia
Rieti 27 ottobre 2006
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HCL: PERIPHERAL BLOOD
CD22HAIRY CELL LEUKEMIA
- Pancytopenia- Dry-tap (marrow fibrosis)- Marked splenomegaly- No lymphadenopathy- Circulating hairy cells
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HAIRY CELL LEUKEMIA: UNSOLVED ISSUES
• ORIGIN OF HCL CELLS
• MORPHOLOGICAL APPEARANCE (HAIRY PROJECTIONS)
• SELECTIVE HOMING OF TUMOR CELLS TO BM, PB, LIVER,
AND SPLEEN (WITH SPARING OF LYMPH NODES)
• PHAGOCYTIC ACTIVITY (LATEX PARTICLES)
• CONSISTENT BONE MARROW FIBROSIS
• DIFFERENTIAL DIAGNOSIS WITH RELATED CONDITIONS (HCL VARIANT, SPLENIC MARGINAL ZONE LYMPHOMA WITH VILLOUS LYMPHOCYTES)
• GOOD RESPONSE TO INTERFERONS AND PURINE ANALOGUES
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<-2 >2 B
HCL BM biopsies
MCLB-CLLDLBCLFLBL
HCLHCL CD19+ enriched
A
Bone marrowsignature
J. Ex. Med 199:59,
2004
HCL SHOWS HOMOGENEOUS SIGNATURE (UNSUPERVISED ANALYSIS)
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THE ORIGIN OF HCL CELLS
POST-GERMINAL CENTER CELLOF UNKNOWN STAGE (GIVEN THE UNIQUE PHENOTYPE OF HCL ) (REAL/WHO)
Somatic IgV mutations (no ongoing)
No GC-related markers
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N&M
GC
0 0.1
-0.1
0.3
0.5
0.7
0.9
-0.3
-0.5
-0.7
-0.9
N&M GC HCL N HCLM M
N
HCL are more related to memory B cells
Pathogenetic implications: Lack of chromosomal translocations (typical of HCL) may be to the fact that the mechanisms generating these aberrations (i.e. VDJ recombination, somatic hypermutation, etc. ) are switched off in memory B cells.
(Basso et al, J Exp Med, 199: 59, 2004)
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- In spite of similarities, a peculiar expression pattern
of cytokines, chemokine receptors and adhesion
molecules, distinguishes HCL from tonsil normal
memory B cells
- this finding might be caused by unknown oncogenic
event(s) leading to HCL or reflect derivation from
a particular subset of memory B cells (splenic mz
B-cells ?)
DIFFERENCES BETWEEN HCL AND MEMORY B CELLS
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N CC HCLCB M
Activation
DNA metabolism
Transcription
Proliferation
- CHC1L
- CCND1
Signaling
- IkB epsilon
- CAMK1
- DGKA
- SIPA1
- IRF4- EGR3
- MADH3- LYL1- ZNF135
Chemokine-receptorsChemokines
Cytokines - IL-6- TNSF11
- CCR7
antiApoptosis
- BIKpro
Cytokine-Receptors- TNFRSF1B
- WSX1
N CC HCLCB M
Adhesion - CD1c
- PCDH9
- GARP- CD9- CD103
- ICAM3
Cellular programs affected by malignant transformation
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HCL: ADHERENCE TO GLASS SURFACE
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ACTINANNEXIN I
PHAGOCYTOSIS MO/MØ FEATURES
• TRAP lysosomal activity
• Expression of Mo/Mø associated molecules: - CD11c - CD68 Mo/Mø-restricted - MIR10 (CD85d)
- Endoglin (CD105)
- CD63 - CPVL
- c-MAF
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HCL-specific genes (n=89)
CB CC N MHCL FL BL B-CLLDLBCL MCL
Normal B cells B cell lymphomas
- ANXA1
- FLT3
- CD63
- SCNB1- SDC3
- FGF2
- CCND1
- IL3Ra
- TIMP1
- MYF6
- PLXNC1
- FGFR1
- PTPRM
- SYT1
- TIMP4- arrestin B
Previously knownIHC performed
- EPB41L2
- CXCR5
- GAS7
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GAS-7
F-ACTIN
OVERLAY
GAS7
• BELONGS TO THE FAMILY OF THE GROWTH-ARREST-SPECIFIC (GAS) PROTEINS
• IS EXPRESSED IN ADULT MOUSE BRAIN AND TESTICLE
• ESSENTIAL FOR NEURITE OUTGROWTH IN CULTURED CEREBELLAR NEURONS
• GAS7 CAN INDUCE THE FORMATION OF EXTENDED CELLULAR PROCESSES IN NIHT3 BY INTERACTING WITH ACTIN AND MEDIATING RE-ORGANIZATION OF MICROFILAMENTS
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(She B-R et al., Exp. Cell Research 273:34-44, 2002)
THE ECTOPIC EXPRESSION OF GAS7 IN NIH3T3 CELLS INDUCES
THE FORMATION OF EXTENSIVE CELLULAR PROCESSES WITH
BRANCHES AND KNOBS, AND SHIRINKAGE OF THE CELL BODY
GAS-7 F-ACTIN OVERLAY
GAS-7 F-ACTIN OVERLAY
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HCL: SPLEEN (pre-IFN era)
HOMING OF HCL CELLS TO SELECTED BOBY SITES
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HCL: LIVER INVOLVEMENT
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SPLEENBASEMENTMEMBRANE
(RING FIBER)
LATERAL FIBER
A NORMAL SINUS
LONGITUDINALRETICULUMFIBERS(CORE FIBERS)
ENDOTHELIALCELL
DEGENERATIVEENDOTHELIALCELL
HAIRY CELL
B PARTIALLY INVOLVED
REDBLOODCELL
CPSEUDOSINUS
D BLOOD LAKE
HAIRY CELLS
Interaction VLA-4 (HCL) / VCAM-1 (sinusoids)
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HCL-specific genes
CB CC N MHCL FL BL B-CLLDLBCL MCL
Normal B cells B cell lymphomas
- ANXA1
- FLT3
- CD63
- SCNB1- SDC3
- FGF2
- CCND1
- IL3Ra
- TIMP1
- MYF6
- PLXNC1
- FGFR1
- PTPRM
- SYT1
- TIMP4- arrestin B
Previously knownIHC performed
- EPB41L2
- CXCR5
- GAS7
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BM
SPLEENRED PULP
PE
RIP
HE
RA
L B
LO
OD
ANNEXIN I
TRANS-ENDOTHELIALMIGRATION
CXCR5 CCR7
HOMING T0LYMPH NODES
- Degradation of the pericellular matrix- Crossing of tissue barriers- Extravasation- Neo-angiogenesis
EN
DO
TH
EL
IUM
HCL REMAINS CONFINED TO BLOOD COMPARTMENTS
EXTRANODALINVOLVEMENT
MMPs ACTIVITY (INVASION AND METASTASIS)
NODAL INVOLVEMENT
TIMP-1TIMP-4RECKTHROMBOSPONDIN-1
(inhibitors of metalloproteases)
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HCL: BONE MARROW FIBROSIS
- BM fibrosis: Fibronectin + argyrophilic reticulin fibers
- HCLs bind to fibronectin
- HCLs synthetize/assemble fibronectin matrix (Burthem)
- Production rate fibronectin under control of autocrine b-FGF secreted by HCLs (Aziz)
- Microarray study confirms up-regulation of b-FGF and FGFR (autocrine loop)
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b-FGF
PRODUCTION OF
FLT3-L
VLA4
VLA5
FIBRONECTINRECEPTORS
ADHESION TO
FIBRONECTIN MATRIX
BM MICRO-ENVIRONMENT
HAIRY CELL
RETICULINFIBROSIS
IL-3
b-FGF
FGFR
HYPOTHETICAL MODEL OF BONE MARROW FIBROSIS IN HCL
IL3R
FLT3
TGF-beta
Collagen III
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OTHER GENES
6.1 (12.0) Gene 1 6.0 (41.5) Gene 2 5.3 (10.1) Gene 3
5.2 (-26.5) Gene 35.1 (-6.4) Unknown 2.7 (-8.5) Gene 4
IMMUNIZATION
PRODUCTION OF mAb
IMMUNOHISTOCHEMISTRY
AVAILABLE ANTIBODY
DISEASE (A) DISEASE (B)
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HCL-specific genes
CB CC N MHCL FL BL B-CLLDLBCL MCL
Normal B cells B cell lymphomas
- ANXA1
- FLT3
- CD63
- SCNB1- SDC3
- FGF2
- CCND1
- IL3Ra
- TIMP1
- MYF6
- PLXNC1
- FGFR1
- PTPRM
- SYT1
- TIMP4- arrestin B
Previously knownIHC performed
- EPB41L2
- CXCR5
- GAS7
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Annexin 1 expression
0
4000
8000
12000
16000
20000
HC
L
CB
CC N M FL
BL
DL
BC
L
MC
L
B-C
LL
Ave
rage
Diff
eren
ce (
MA
S5.
0)
Annexin 1 expression
0
4000
8000
12000
16000
20000
HC
L
CB
CC N M FL
BL
DL
BC
L
MC
L
B-C
LL
Ave
rage
Diff
eren
ce (
MA
S5.
0)
- ANXA1: REGULATION OF EARLY INFLAMMATORY RESPONSES (INHIBITION OF ADHESION,
MIGRATION, ETC.)
- ANXA1 BINDS TO ACTIN FIBERS (CYTOSKELETON) - EXPRESSED IN MYELOID CELLS, STROMAL CELLS, MACROPHAGES, SUBSET T CELLS
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ANXA1 PROTEIN EXPRESSION IN B-CELL LYMPHOMAS
LYMPHOMA TYPE N=500 ANXA1
HCL 64 62/64*
HCL variant (HCLv) 8 0/8
B-CLL 80 0/80
Prolymphocytic leukemia 3 0/3
Splenic MZL** 50 0/50
Nodal MZL 15 0/15
Lymphoplasmocytic lymphoma 30 0/30
Follicular lymphoma 65 0/65
Mantle cell lymphoma 14 0/14
DLCL-B 100 0/100
Burkitt lymphoma 10 0/10
Myeloma 50 0/50
* Two cases turn out to be HCLv; ** With and without circulating villous lymphocytes
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HAIRY CELL LEUKEMIA
HCL cell Annexin A1
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CLASSIC HODGKIN’S DISEASE
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B-CELL LYMPHOMAS SIMULATING HCL
• HCL-VARIANT (HCLv)
• LYMPHOCYTES (SLVL) SPLENIC LYMPHOMA
WITH VILLOUS
• OTHER LYMPHOMAS WITH CIRCULATING
VILLOUS LYMPHOCYTES
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Biphasic morphology
Villous lymphocytes
Splenic MZL 1% of all lymphomas
Indolent tumor
Leukemic phase: Villous lymphocytes
Phenotype: Similar to HCL
Genetic: Allelic loss 7q31-32 (SLVL)
Clinic: Splenomegaly
HCV+ SLVL respond to IFN
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Falini B., Lancet 363:1869, 2004
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SLVL: INTRASINUSOIDAL PATTERN (CD79a)
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SLVL (Annexin A1)
*
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CONCLUSIONS
• HCL DISPLAYS A DISTINCTIVE AND HOMOGENOUS GEP SUGGESTING THAT IT IS A SINGLE DISEASE, CONSISTENT WITH ITS HOMOGENOUS MORPHOLOGY AND CLINICAL BEHAVIOUR
• HCL SIGNATURE IS MORE RELATED TO MEMORY B CELLS THAN TO NAIVE AND GERMINAL CENTER B CELLS, OR LYMPHOBLASTOID B CELLS AND PLASMA CELLS
• HCL DIFFERS FROM MEMORY B CELLS MAINLY IN THE EXPRESSION OF CYTOKINES, CHEMOKINE RECEPTORS AND ADHESION MOLECULES
• GEP ANALYSIS IDENTIFIES 89 GENES WHICH ARE SPECIFICALLY UP- OR DOWN-REGULATED IN HCL. THEY ARE POSSIBLY RESPONSIBLE FOR THE DISTINCTIVE FEATURES OF HCL CELLS ( EXPERIMENTAL VALIDATION REQUIRED)
• INFORMATION OF GEP HAS BEEN ALREADY TRANSLATED INTO A SPECIFIC, CLINICALLY USEFUL ANNEXIN A1-BASED IMMUNOASSAY
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BRUNANGELO FALINI (PERUGIA UNIVERSITY)
ENRICO TIACCI (PERUGIA UNIVERSITY)
ROBERTA BENEDETTI (PERUGIA UNIVERSITY)
ELENA SABBATINI (BOLOGNA UNIVERSITY)
STEFANO PILERI (BOLOGNA UNIVERSITY)
ALESSANDRO PULSONI ( ROME UNIVERSITY)
ROBIN FOA (ROME UNIVERSITY)
FRANCESCO DI RAIMONDO (CATANIA UNIVERSITY)
ACHILLE AMBROSETTI (VERONA UNIVERSITY)
KATIA BASSO (COLUMBIA UNIVERSITY)
RICCARDO DALLA FAVERA(COLUMBIA UNIVERSITY)
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IMMUNOPHENOTYPE OF CHRONIC B-CELL LEUKEMIAS
Antigen CLL HCL SLVL
CD5 + + - - CD23 ++ - -
FMC7 ± + + + +
CD10 - - -
CD25 - + + -/+
CD68 - + -/+
CD11c -/+ + +
DBA44 - + +
CD103 - -/+ -
ANNEXIN A1 - +++ -