Sorger, Helena ORCID: 0000-0002-3380-7770, Dey, Saptaswa ORCID: 0000-0001-7532-7858, Vieyra-Garcia, Pablo Augusto, Poeloeske, Daniel, Teufelberger, Andrea R., de Araujo, Elvin D., Sedighi, Abootaleb, Graf, Ricarda, Spiegl, Benjamin ORCID: 0000-0003-4497-6120, Lazzeri, Isaac ORCID: 0000-0002-3609-3443, Braun, Till, Alonso, Ines Garces de Los Fayos, Schlederer, Michaela, Timelthaler, Gerald, Kodajova, Petra, Pirker, Christine, Surbek, Marta, Machtinger, Michael, Graier, Thomas, Perchthaler, Isabella, Pan, Yi, Fink-Puches, Regina, Cerroni, Lorenzo, Ober, Jennifer, Otte, Moritz, Albrecht, Jana D., Tin, Gary, Abdeldayem, Ayah, Manaswiyoungkul, Pimyupa, Olaoye, Olasunkanmi O., Metzelder, Martin L., Orlova, Anna, Berger, Walter, Wobser, Marion, Nicolay, Jan P., Andre, Fiona, Nguyen, Van Anh, Neubauer, Heidi A., Fleck, Roman, Merkel, Olaf, Herling, Marco, Heitzer, Ellen, Gunning, Patrick T., Kenner, Lukas ORCID: 0000-0003-2184-1338, Moriggl, Richard and Wolf, Peter (2022). Blocking STAT3/5 through direct or upstream kinase targeting in leukemic cutaneous T-cell lymphoma. EMBO Mol. Med., 14 (12). HOBOKEN: WILEY. ISSN 1757-4684

Full text not available from this repository.

Abstract

Leukemic cutaneous T-cell lymphomas (L-CTCL) are lymphoproliferative disorders of skin-homing mature T-cells causing severe symptoms and high mortality through chronic inflammation, tissue destruction, and serious infections. Despite numerous genomic sequencing efforts, recurrent driver mutations have not been identified, but chromosomal losses and gains are frequent and dominant. We integrated genomic landscape analyses with innovative pharmacologic interference studies to identify key vulnerable nodes in L-CTCL. We detected copy number gains of loci containing the STAT3/5 oncogenes in 74% (n = 17/23) of L-CTCL, which correlated with the increased clonal T-cell count in the blood. Dual inhibition of STAT3/5 using small-molecule degraders and multi-kinase blockers abolished L-CTCL cell growth in vitro and ex vivo, whereby PAK kinase inhibition was specifically selective for L-CTCL patient cells carrying STAT3/5 gains. Importantly, the PAK inhibitor FRAx597 demonstrated encouraging anti-leukemic activity in vivo by inhibiting tumor growth and disease dissemination in intradermally xenografted mice. We conclude that STAT3/5 and PAK kinase interaction represents a new therapeutic node to be further explored in L-CTCL.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Sorger, HelenaUNSPECIFIEDorcid.org/0000-0002-3380-7770UNSPECIFIED
Dey, SaptaswaUNSPECIFIEDorcid.org/0000-0001-7532-7858UNSPECIFIED
Vieyra-Garcia, Pablo AugustoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Poeloeske, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Teufelberger, Andrea R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Araujo, Elvin D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sedighi, AbootalebUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Graf, RicardaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spiegl, BenjaminUNSPECIFIEDorcid.org/0000-0003-4497-6120UNSPECIFIED
Lazzeri, IsaacUNSPECIFIEDorcid.org/0000-0002-3609-3443UNSPECIFIED
Braun, TillUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alonso, Ines Garces de Los FayosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schlederer, MichaelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Timelthaler, GeraldUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kodajova, PetraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pirker, ChristineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Surbek, MartaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Machtinger, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Graier, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perchthaler, IsabellaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pan, YiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fink-Puches, ReginaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cerroni, LorenzoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ober, JenniferUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Otte, MoritzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Albrecht, Jana D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tin, GaryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Abdeldayem, AyahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Manaswiyoungkul, PimyupaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Olaoye, Olasunkanmi O.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Metzelder, Martin L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Orlova, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Berger, WalterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wobser, MarionUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nicolay, Jan P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Andre, FionaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nguyen, Van AnhUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neubauer, Heidi A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fleck, RomanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Merkel, OlafUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herling, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heitzer, EllenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gunning, Patrick T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kenner, LukasUNSPECIFIEDorcid.org/0000-0003-2184-1338UNSPECIFIED
Moriggl, RichardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolf, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-692753
DOI: 10.15252/emmm.202115200
Journal or Publication Title: EMBO Mol. Med.
Volume: 14
Number: 12
Date: 2022
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1757-4684
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MYCOSIS-FUNGOIDES; PROGNOSTIC-FACTORS; SEZARY-SYNDROME; EXPRESSION; APOPTOSIS; PHOSPHORYLATION; RESISTANCE; MUTATIONS; LANDSCAPE; GROWTHMultiple languages
Medicine, Research & ExperimentalMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69275

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item