PTCL Teresa Palomero, PhD Institute for Cancer Genetics Department - - PowerPoint PPT Presentation

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Sep 09, 2022 803 likes •1.02k views

Molecular genotyping in PTCL Teresa Palomero, PhD Institute for Cancer Genetics Department of Pathology and Cell Biology Herbert Irving Comprehensive Cancer Center Columbia University Medical Center Recurrent mutations in AITL and PTCL, NOS

SLIDE 1

Teresa Palomero, PhD

Institute for Cancer Genetics Department of Pathology and Cell Biology Herbert Irving Comprehensive Cancer Center Columbia University Medical Center

Molecular genotyping in PTCL

SLIDE 2

Recurrent mutations in AITL and PTCL, NOS

IDH2

NH2 452

R172K

DNMT3A

D702N L650Q N838D R736C R882H V690D

NH2 PHD Methyltransferase 912

L648P N879D

PWWP NH2

TET2

Cys DSBH

2002

S1870L C1221Y L1340R L1378F H1380L H1881R C1273F S1898F

Epigenetic regulators TCR signaling pathway

SLIDE 3

Recurrent activating FYN kinase mutations in PTCL

P-SRC

(Palomero, Couronne et al., Nat Genet 2014)

SLIDE 4

Mechanisms of FYN constitutive activation in PTCL

SH2 SH3

CSK

SH3 SH2

Inactive Active

FYN-SH2 Input

(Palomero, Couronne et al., Nat Genet 2014)

SLIDE 5

Dasatinib (BMS-354825)

Inhibition of oncogenic mutant FYN activity by Dasatinib

(Palomero, Couronne et al., Nat Genet 2014)

SLIDE 6

AITL PTCL−NOS ALCL NK

VAV1 ALK CREBBP CCND3 STAT6 STAT5B JAK1 STAT3 TP53 PRDM1 PLCG1 VAV1 ATM CARD11 DNMT3A FYN CD28 IDH2 TET2 RHOA

Gene fusions Mutations

Frameshift Stop gain Missense In-frame deletion In-frame gene fusion

Identification of frequent alterations in VAV1 in PTCL

(Abate, da Silva Almeida et al., PNAS 2017)

SLIDE 7

CH Ac DH PH C1 SH3 SH2 SH3 845

NH2 VAV1

941 NH2

CH Ac DH PH C1 SH 3 SH2

VAV1-THAP4

nitrobindin

VAV1 THAP4

A GA GA A CCATCA GCA GGCCA GCA GA GCCCCCCA A GATGA A CCCA GTG

VAV1 MYO1F

A GA GA A CCATCA GCA GGCCA GCA GA GCC TA CGCGGA A GGGA ATGGCC

952 NH2

CH Ac DH PH C1 SH 3 SH2 S H 3

VAV1-MYO1F 884 NH2

CH Ac DH PH C1 SH 3 SH2

VAV1-S100A7

EF1 EF2 A GA GA A CCATCA GCA GGCCA GCA GGCTT TT TGA A A GCA A A GATGA GCA A

VAV1 S100A7

A B C D

C-terminal VAV1 gene fusions in PTCL

(Abate, da Silva Almeida et al., PNAS 2017)

SLIDE 8

VAV1 splice site deletions induce alternative splicing by eliminating an exonic silencer

(Abate, da Silva Almeida et al., PNAS 2017)

SLIDE 9

Deletions affecting the c-terminal SH3 domain of VAV1 induce an open active conformation of the protein

(Abate, da Silva Almeida et al., PNAS 2017)

SLIDE 10

Recurrent mutations in RHOA in PTCL

PTCL PTCL NOS AITL

(Palomero et al., Nat Genet 2014)

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RHOA G17V impairs RHOA activation by interfering with RHOA pathway activation

Cytoskeleton remodeling
Migration
Receptor signaling regulation

F-ACTIN ROCK

RHO-GEF RHOA RHO-GAP RHOA RHOA G17V

GTP GTP GDP

CD28 CD3 FYN LCK ZAP70 TCR CD4

b g

RHOA G17V

does not upload GTP
does not interact with effectors
has high affinity for RHO-GEFs

(Palomero et al., Nat Genet 2014)

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