Chicago, Sept 9, 2017 Society of Hematopathology Workshop Molecular Genetics of Hematopoietic Neoplasms Kojo S. J. Elenitoba-Johnson MD Peter Nowell MD Professor Director, Division of Precision and Computational Diagnostics Department of Pathology and Laboratory Medicine University of Pennsylvania Novel Insights into the Molecular Pathogenesis of T-cell Lymphomas
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Novel Insights into the Molecular Pathogenesis of T -cell ... · 2016 World Health Organization . Mature T-cell neoplasms. Cutaneous. Primary cutaneous CD8+ aggressive epidermotropic
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Chicago, Sept 9, 2017
Society of Hematopathology Workshop Molecular Genetics of Hematopoietic Neoplasms
Kojo S. J. Elenitoba-Johnson MDPeter Nowell MD Professor
Director, Division of Precision and Computational DiagnosticsDepartment of Pathology and Laboratory Medicine
University of Pennsylvania
Novel Insights into the Molecular Pathogenesis of T-cell Lymphomas
Disclosure
GENOMENON: Co-Founder
OutlineBackground
• WHO classification of mature T cell lymphoma
Recent updates in genetics of T cell lymphoma
• PTCL/AITL• CTCL/SS• ALCL
• Pathobiologic and therapeutic implications
• Conclusions
OutlineBackground
• WHO classification of mature T cell lymphoma
Recent updates in genetics of T cell lymphoma
• PTCL/AITL• CTCL/SS• ALCL
• Pathobiologic and therapeutic implications
• Conclusions
2016 World Health Organization
Mature T-cell neoplasms
Cutaneous
Primary cutaneous CD8+ aggressive epidermotropic
cytotoxic TCL*
Primary cutaneous CD4+ small/medium T cell
lymphoproliferative disorder*
Primary cutaneous γδ TCL
Primary cutaneous ALCL
Primary cutaneous CD30+ T-cell Disorders
Sézary syndrome
Mycosis fungoides (MF)
ExtranodalNK/TCL nasal type
Enteropathy-associated TCL
Hepatosplenic TCL
Subcutaneous Panniculitis-Like TCL
Systemic EBV+ T-cell lymphoproliferative
disorder of childhood
Hydroa vacciniforme-like
NodalPeripheral TCL-NOS
Anaplastic large Cell lymphoma (ALK +)
Anaplastic Large Cell lymphoma (ALK -)
AngioimmunoblasticTCL
LeukemicAdult T-cell
leukemia/lymphoma
T-cell prolymphocyticleukemia
T-cell large granular lymphocytic leukemia
*Provisional entity.
Aggressive NK-cell leukemia
Chronic lymphoproliferativedisorder of NK cells*
Monomorphic epitheliotropic intestinal T-
cell lymphoma*
Primary cutaneous acralCD8+ TCL*
Follicular T cell lymphoma*
Nodal peripheral T cell lymphoma with TFH
phenotype*
Breast implant-associated ALCL*
Relative frequencies of mature T-cell lymphomas
International T-Cell Lymphoma Project
1. Vose JM et al. J Clin Oncol. 2008;26(25):4124-4130.
Subclassification of PTCL and Survival
International T-Cell Lymphoma Project. J Clin Oncol. 2008;26(25):4124-4130.
Molecular diagnostic signatures of TCL subgroups
8
Iqbal J et al., Blood Rev 2016
Diagnostic and biologic gray zones in PTCL
Markers to consider:
• Morphologic, immunophenotypic and genetic overlap
• Malignancy of post-thymic T-cells characterized by triad of erythroderma, lymphadenopathy, pruritus
• Complex karyotypes without recurrent structural variants
19
SÉZARY SYNDROME
Whole Genome Sequencing Confirms Complexity of Sézary Syndrome Genomes
20Kiel M, et al. Nat Commun 2015
Exome Sequencing Identifies Regions of Recurrent Aneuploidy in 74 Sézary Patients• 1p36.11• 3p21.31• 9p21.3• 10p11.22• 10q23.31• 10q21.2• 13q14.2• 17p• 19p
TP53
CDKN2A21
RB1
PTEN
Loss of Function of ARID1A in Sézary Genomes (25/62; 40%)
22
ARID1a inactivation detected by immunocytochemistry
Loss of Function of TET1/2 in Sézary Genomes (38/62; 61%)
24
Epigenetic Modifiers are Targeted by Aneuploidy and Mutation in Sézary Genomes
25
Choi J et al Nat Genet. 2015 Sep;47(9):1011-9Wang L et al Nat Genet. 2015 Dec;47(12):1426-34da Silva Almeida AC et al Nat Genet. 2015 Dec;47(12):1465-70Ungewickell A et al Nat Genet. 2015 Sep;47(9):1056-60.
DNMT EZH2BMI1PRC
HDAC
KDM6B
TRX ARID, SMARMLL, SETD
CDKN2A/BTET1/2
H3K27Me2/3
H3K4Me2/3
Xp16
p19
MLL
CCNDCDK4CCNDCDK6
p53 p21
E2F
RB1
X
Cell cycle progression
Cell cycle arrest
STAT3
εεδ γ
CD4
TCR/CD3
PLCγ1LA
T
MYC
ARID1A
ZAP70
IP3 DAG
[CA++]
Calcineurin
NFAT
RAS
MAPK
c-FOSAP-1
c-JUN
PKCθ CARMA1MALT1
BCL10
IKKNFκBNFκB
STAT5
ZEB1
~15%
~40%
~40%
~25%
~40%
~12%
~47%
~50%
NCOR~50%
~92%
~45%
~67%
~11%
~9%
IL-2
JAK1/3
RII
TGFβ
RI
Smad 2
P
P
Smad 3
P
PP
PDCD1~36%
~25%
~26%
RB1MDM2
TRAF3
DDDD
TNF
TRAF2
kinase
TRADD TRADD
DD
RIP
A20
R2R2
R2~18%
~25%
FAS-L
Apoptosis
FAS
ATM
Genotoxic stress
~30%
P
P
P
TAB2
TAK1
TAB1
P
P
P
CD80/86
PP
Lck
* CTLA4-CD28
GRB2 Y
ITK
Loss of Function
Gain of Function
Growth ArrestCell Proliferation
PI3
K
PIP2 PIP3
PTEN
AKT
~36%
STAT3P
STAT5P
IL2R
• Genomic complexity
• Somatic mutations in chromatin remodelers and epigenetic modifiers (ARID1A, TET2, DNMT3A)
• Mutations in oncogenic drivers coexist in neoplastic cells (JAK1/3, STAT3/5)