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

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 Epigenetic regulators C1221Y C1273F H1881R L1340R L1378F H1380L S1870L S1898F TET2 NH2 2002 Cys DSBH R882H D702N R736C N838D L650Q V690D N879D DNMT3A L648P NH2 PWWP PHD Methyltransferase 912 R172K IDH2 NH2 452 TCR signaling pathway

Recurrent activating FYN kinase mutations in PTCL P-SRC (Palomero, Couronne et al ., Nat Genet 2014)

Mechanisms of FYN constitutive activation in PTCL CSK SH3 SH3 SH2 SH2 P Active Inactive FYN-SH2 Input (Palomero, Couronne et al ., Nat Genet 2014)

Inhibition of oncogenic mutant FYN activity by Dasatinib Dasatinib (BMS-354825) (Palomero, Couronne et al ., Nat Genet 2014)

Identification of frequent alterations in VAV1 in PTCL PTCL − NOS Gene fusions AITL ALCL NK ALK VAV1 Mutations RHOA TET2 IDH2 CD28 FYN DNMT3A CARD11 ATM VAV1 PLCG1 PRDM1 TP53 STAT3 JAK1 STAT5B STAT6 CCND3 CREBBP Frameshift Stop gain Missense In-frame deletion In-frame gene fusion (Abate, da Silva Almeida et al ., PNAS 2017)

C-terminal VAV1 gene fusions in PTCL A VAV1 NH2 SH3 845 CH Ac DH PH C1 SH3 SH2 B 884 VAV1-S100A7 NH2 Ac DH PH C1 SH 3 SH2 EF1 EF2 CH VAV1 S100A7 A GA GA A CCATCA GCA GGCCA GCA GGCTT TT TGA A A GCA A A GATGA GCA A C 941 VAV1-THAP4 NH2 nitrobindin CH Ac DH PH C1 SH 3 SH2 VAV1 THAP4 A GA GA A CCATCA GCA GGCCA GCA GA GCCCCCCA A GATGA A CCCA GTG D VAV1-MYO1F NH2 952 CH Ac DH PH C1 SH 3 SH2 S H 3 VAV1 MYO1F A GA GA A CCATCA GCA GGCCA GCA GA GCC TA CGCGGA A GGGA ATGGCC (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 TCR CD4 CD28 CD3 RHOA G17V • does not upload GTP • does not interact with effectors ZAP70 G a b • LCK FYN has high affinity for RHO-GEFs g RHO-GEF RHOA G17V F-ACTIN GTP • Cytoskeleton remodeling RHOA RHOA • Migration GDP GTP • Receptor signaling regulation P ROCK RHO-GAP (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. Jose R. Cortes Dr. Stefano Pileri Dr. Maria Antonella Laginestra Dr. Ana da Silva Almeida Anisha Cooke Dr. Ross Levine Dr. Adolfo Ferrando Dr. Lucile Couronne S. Aidan Quinn Dr. Iannis Aifantis Dr. Marta Sanchez Martin Christine S. Kim Dr. Mi-Yeon Kim Dr. Ari Melnick Dr. Raul Rabadan Dr. Giorgio Inghirami Dr. Francesco Abate Dr. Danilo Fiore Sakellarios Zairis Dr. Joan Guitart Dr. Hossein Khiabanian Dr. Estela Martinez Dr. Larisa Geskin Christina Patrone Dr. Govind Bhagat Dr. Olivier A. Bernard Dr. Xosé R Bustelo Dr. Elias Campo Javier Robles-Valero Dr. Miguel Angel Piris Dr. Izidore Lossos