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

Recurrent mutations in AITL and PTCL, NOS

IDH2

NH2 452

R1

72

K

DNMT3A

D7

02

N

L6

50

Q

N8

38

D

R7

36

C

R8

82

H

V6

90

D

NH2 PHD Methyltransferase 912

L6

48P

N8

79D

PWWP

RHOA

G1

7V

,G

17

EC

16

R

D1

20

Y

CAAXNKxD

NH2

TET2

Cys DSBH 2002

S1

870

L

C12

21

Y

L1

34

0R

L1

378

FH

138

0L

H18

81

R

C127

3F

S1

898

F

T1

9I

NH2 GG Effector 193

CD28

NH2 220

D124E

,D

124V

NH2 537

R1

76

C

Immunoglobulin domain

T195P

,T

195I

FYN

SH2SH3 Kinase domain

Y5

31

H

L1

74

R

TML S2

S3

Epig

enet

ic r

egu

lato

rsTC

R s

ign

alin

g p

ath

way

Recurrent activating FYN kinase mutations in PTCL

P-SRC

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

Mechanisms of FYN constitutive activation in PTCL

P

SH2

SH3

CSK

SH3

SH2

InactiveActive

FYN-SH2

Input

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

Dasatinib (BMS-354825)

Inhibition of oncogenic mutant FYN activity by Dasatinib

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

AITL PTCL−NOS ALCL NK

VAV1ALK

CREBBPCCND3STAT6

STAT5BJAK1

STAT3TP53

PRDM1PLCG1

VAV1ATM

CARD11DNMT3A

FYNCD28IDH2TET2

RHOA

Gene fusions

Mutations

FrameshiftStop gainMissenseIn-frame deletionIn-frame gene fusion

Identification of frequent alterations in VAV1 in PTCL

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

CH Ac DH PH C1 SH3 SH2 SH3 845NH2VAV1

941NH2 CH Ac DH PH C1 SH3 SH2VAV1-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

952NH2 CH Ac DH PH C1 SH3 SH2 SH3VAV1-MYO1F

884NH2 CH Ac DH PH C1 SH3 SH2VAV1-S100A7 EF1 EF2

A GA GA A CCATCA GCA GGCCA GCA GGCT T T T 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)

VAV1 splice site deletions induce alternative splicing

by eliminating an exonic silencer

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

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)

Recurrent mutations in RHOA in PTCL

PTCL PTCL NOS AITL

(Palomero et al., Nat Genet 2014)

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

P

GTP

GTPGDP

CD28

CD3

FYNLCKZAP70

TCR CD4

Ga bg

RHOA G17V

• does not upload GTP

• does not interact with effectors

• has high affinity for RHO-GEFs

(Palomero et al., Nat Genet 2014)

Tamoxifen-induced expression of Rhoa G17V

in CD4+ cells leads to TFH differentiation

(Cortes et al., Cancer Cell 2018)

Rhoa G17V CD4+ T-cells show increased

expression of Tfh markers

(Cortes et al., Cancer Cell 2018)

Rhoa G17V increases the activity of ICOS-regulated

signaling pathways in vitro

(Cortes et al., Cancer Cell 2018)

Expression of RHOA G17V in a Tet2 null

background leads to AITL development

(Cortes et al., Cancer Cell 2018)

Inhibition of ICOS signaling blocks AITL growth in vivo

(Cortes et al., Cancer Cell 2018)

(Cortes et al., Cancer Cell 2018)

RHO GTPases pathways play a key role in PTCL

ICOS

FYN

VAV1

RHOA

Acknowledgements

Dr. Stefano Pileri

Dr. Maria Antonella Laginestra

Dr. Ross Levine

Dr. Iannis Aifantis

Dr. Ari Melnick

Dr. Giorgio Inghirami

Dr. Danilo Fiore

Dr. Joan Guitart

Dr. Estela Martinez

Dr. Govind Bhagat

Dr. Olivier A. Bernard

Dr. Elias Campo

Dr. Miguel Angel Piris

Dr. Izidore Lossos

Dr. Jose R. Cortes

Dr. Ana da Silva Almeida

Anisha Cooke

Dr. Adolfo Ferrando

Dr. Lucile Couronne

S. Aidan Quinn

Dr. Marta Sanchez Martin

Christine S. Kim

Dr. Mi-Yeon Kim

Dr. Raul Rabadan

Dr. Francesco Abate

Sakellarios Zairis

Dr. Hossein Khiabanian

Dr. Larisa Geskin

Christina Patrone

Dr. Xosé R Bustelo

Javier Robles-Valero

http://www.lls.org/http://www.lls.org/