High activation of STAT5A drives peripheral T-cell lymphoma and
leukemia

J 2020

High activation of STAT5A drives peripheral T-cell lymphoma and leukemia

MAURER, B., H. NIVARTHI, B. WINGELHOFER, H. T. T. PHAM, M. SCHLEDERER et. al.

Basic information

Original name

High activation of STAT5A drives peripheral T-cell lymphoma and leukemia

Authors

MAURER, B. (40 Austria), H. NIVARTHI (40 Austria), B. WINGELHOFER (40 Austria), H. T. T. PHAM (40 Austria), M. SCHLEDERER (40 Austria), T. SUSKE (40 Austria), R. GRAUSENBURGER (40 Austria), A. I. SCHIEFER (40 Austria), M. PRCHAL-MURPHY (40 Austria), D. CHEN (40 Austria), S. WINKLER (40 Austria), O. MERKEL (40 Austria), C. KORNAUTH, M. HOFBAUER (40 Austria), B. HOCHGATTERER (40 Austria), G. HOERMANN (40 Austria), A. HOELBL-KOVACIC (40 Austria), J. PROCHAZKOVA (40 Austria), Cosimo LOBELLO (380 Italy, belonging to the institution), A. A. CUMARASWAMY (124 Canada), J. LATZKA (124 Canada), M. KITZWOGERER (40 Austria), A. CHOTT (40 Austria), Andrea JANÍKOVÁ (203 Czech Republic, belonging to the institution), Šárka POSPÍŠILOVÁ (203 Czech Republic, guarantor, belonging to the institution), J. I. LOIZOU (40 Austria), S. KUBICEK (40 Austria), P. VALENT (40 Austria), T. KOLBE (40 Austria), F. GREBIEN (40 Austria), L. KENNER (40 Austria), P. T. GUNNING (826 United Kingdom of Great Britain and Northern Ireland), R. KRALOVICS (40 Austria), M. HERLING (276 Germany), M. MULLER (40 Austria), T. RULICKE (40 Austria), V. SEXL (40 Austria) and R. MORIGGL (40 Austria)

Edition

Haematologica, PAVIA, FERRATA STORTI FOUNDATION, 2020, 0390-6078

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30205 Hematology

Country of publisher

Italy

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 9.941

RIV identification code

RIV/00216224:14740/20:00116030

Organization unit

Central European Institute of Technology

DOI

http://dx.doi.org/10.3324/haematol.2019.216986

UT WoS

000510846700034

Keywords in English

EXPRESSION; MUTATIONS; SIGNATURES; LANDSCAPE; DIAGNOSIS; GENETICS; SYSTEMS; MODELS; SIGNAL; ALPHA

Abstract

V originále

Recurrent gain-of-function mutations in the transcription factors S7AT5A and much more in STAT5B were found in hematopoietic malignancies with the highest proportion in mature T- and natural killer-cell neoplasms (peripheral T-cell lymphoma, PTCL). No targeted therapy exists for these heterogeneous and often aggressive diseases. Given the shortage of models for PTCL, we mimicked graded STAT5A or STAT5B activity by expressing hyperactive Stat5a or STAT5B variants at low or high levels in the hematopoietic system of transgenic mice. Only mice with high activity levels developed a lethal disease resembling human PTCL. Neoplasia displayed massive expansion of CD8(+) T cells and destructive organ infiltration. T cells were cytokine-hypersensitive with activated memory CD8(+). T-lymphocyte characteristics. Histopathology and mRNA expression profiles revealed close correlation with distinct subtypes of PTCL. Pronounced STAT5 expression and activity in samples from patients with different subsets underline the relevance of JAK/STAT as a therapeutic target. JAK inhibitors or a selective STAT5 SH2 domain inhibitor induced cell death and ruxolitinib blocked T-cell neoplasia in vivo. We conclude that enhanced STAT5A or STAT5B action both drive PTCL development, defining both STAT5 molecules as targets for therapeutic intervention.

Links

675712, interní kód MU

Name: ALK Activation as a target of TRAanslational Science (ALKATRAS): Break free from cancer (Acronym: ALKATRAS)

Investor: European Union, MSCA Marie Skłodowska-Curie Actions (Excellent Science)

Citovat

MAURER, B., H. NIVARTHI, B. WINGELHOFER, H. T. T. PHAM, M. SCHLEDERER, T. SUSKE, R. GRAUSENBURGER, A. I. SCHIEFER, M. PRCHAL-MURPHY, D. CHEN, S. WINKLER, O. MERKEL, C. KORNAUTH, M. HOFBAUER, B. HOCHGATTERER, G. HOERMANN, A. HOELBL-KOVACIC, J. PROCHAZKOVA, Cosimo LOBELLO, A. A. CUMARASWAMY, J. LATZKA, M. KITZWOGERER, A. CHOTT, Andrea JANÍKOVÁ, Šárka POSPÍŠILOVÁ, J. I. LOIZOU, S. KUBICEK, P. VALENT, T. KOLBE, F. GREBIEN, L. KENNER, P. T. GUNNING, R. KRALOVICS, M. HERLING, M. MULLER, T. RULICKE, V. SEXL and R. MORIGGL. High activation of STAT5A drives peripheral T-cell lymphoma and leukemia. Haematologica. PAVIA: FERRATA STORTI FOUNDATION, 2020, vol. 105, No 2, p. 435-447. ISSN 0390-6078. Available from: https://dx.doi.org/10.3324/haematol.2019.216986.

@article{1670624,
   author = {Maurer, B. and Nivarthi, H. and Wingelhofer, B. and Pham, H. T. T. and Schlederer, M. and Suske, T. and Grausenburger, R. and Schiefer, A. I. and PrchalandMurphy, M. and Chen, D. and Winkler, S. and Merkel, O. and Kornauth, C. and Hofbauer, M. and Hochgatterer, B. and Hoermann, G. and HoelblandKovacic, A. and Prochazkova, J. and Lobello, Cosimo and Cumaraswamy, A. A. and Latzka, J. and Kitzwogerer, M. and Chott, A. and Janíková, Andrea and Pospíšilová, Šárka and Loizou, J. I. and Kubicek, S. and Valent, P. and Kolbe, T. and Grebien, F. and Kenner, L. and Gunning, P. T. and Kralovics, R. and Herling, M. and Muller, M. and Rulicke, T. and Sexl, V. and Moriggl, R.},
   article_location = {PAVIA},
   article_number = {2},
   doi = {http://dx.doi.org/10.3324/haematol.2019.216986},
   keywords = {EXPRESSION; MUTATIONS; SIGNATURES; LANDSCAPE; DIAGNOSIS; GENETICS; SYSTEMS; MODELS; SIGNAL; ALPHA},
   language = {eng},
   issn = {0390-6078},
   journal = {Haematologica},
   title = {High activation of STAT5A drives peripheral T-cell lymphoma and leukemia},
   url = {http://www.haematologica.org/content/haematol/105/2/435.full.pdf},
   volume = {105},
   year = {2020}
}

TY  - JOUR
ID  - 1670624
AU  - Maurer, B. - Nivarthi, H. - Wingelhofer, B. - Pham, H. T. T. - Schlederer, M. - Suske, T. - Grausenburger, R. - Schiefer, A. I. - Prchal-Murphy, M. - Chen, D. - Winkler, S. - Merkel, O. - Kornauth, C. - Hofbauer, M. - Hochgatterer, B. - Hoermann, G. - Hoelbl-Kovacic, A. - Prochazkova, J. - Lobello, Cosimo - Cumaraswamy, A. A. - Latzka, J. - Kitzwogerer, M. - Chott, A. - Janíková, Andrea - Pospíšilová, Šárka - Loizou, J. I. - Kubicek, S. - Valent, P. - Kolbe, T. - Grebien, F. - Kenner, L. - Gunning, P. T. - Kralovics, R. - Herling, M. - Muller, M. - Rulicke, T. - Sexl, V. - Moriggl, R.
PY  - 2020
TI  - High activation of STAT5A drives peripheral T-cell lymphoma and leukemia
JF  - Haematologica
VL  - 105
IS  - 2
SP  - 435-447
EP  - 435-447
PB  - FERRATA STORTI FOUNDATION
SN  - 03906078
KW  - EXPRESSION
KW  - MUTATIONS
KW  - SIGNATURES
KW  - LANDSCAPE
KW  - DIAGNOSIS
KW  - GENETICS
KW  - SYSTEMS
KW  - MODELS
KW  - SIGNAL
KW  - ALPHA
UR  - http://www.haematologica.org/content/haematol/105/2/435.full.pdf
L2  - http://www.haematologica.org/content/haematol/105/2/435.full.pdf
N2  - Recurrent gain-of-function mutations in the transcription factors S7AT5A and much more in STAT5B were found in hematopoietic malignancies with the highest proportion in mature T- and natural killer-cell neoplasms (peripheral T-cell lymphoma, PTCL). No targeted therapy exists for these heterogeneous and often aggressive diseases. Given the shortage of models for PTCL, we mimicked graded STAT5A or STAT5B activity by expressing hyperactive Stat5a or STAT5B variants at low or high levels in the hematopoietic system of transgenic mice. Only mice with high activity levels developed a lethal disease resembling human PTCL. Neoplasia displayed massive expansion of CD8(+) T cells and destructive organ infiltration. T cells were cytokine-hypersensitive with activated memory CD8(+). T-lymphocyte characteristics. Histopathology and mRNA expression profiles revealed close correlation with distinct subtypes of PTCL. Pronounced STAT5 expression and activity in samples from patients with different subsets underline the relevance of JAK/STAT as a therapeutic target. JAK inhibitors or a selective STAT5 SH2 domain inhibitor induced cell death and ruxolitinib blocked T-cell neoplasia in vivo. We conclude that enhanced STAT5A or STAT5B action both drive PTCL development, defining both STAT5 molecules as targets for therapeutic intervention.
ER  -

MAURER, B., H. NIVARTHI, B. WINGELHOFER, H. T. T. PHAM, M. SCHLEDERER, T. SUSKE, R. GRAUSENBURGER, A. I. SCHIEFER, M. PRCHAL-MURPHY, D. CHEN, S. WINKLER, O. MERKEL, C. KORNAUTH, M. HOFBAUER, B. HOCHGATTERER, G. HOERMANN, A. HOELBL-KOVACIC, J. PROCHAZKOVA, Cosimo LOBELLO, A. A. CUMARASWAMY, J. LATZKA, M. KITZWOGERER, A. CHOTT, Andrea JANÍKOVÁ, Šárka POSPÍŠILOVÁ, J. I. LOIZOU, S. KUBICEK, P. VALENT, T. KOLBE, F. GREBIEN, L. KENNER, P. T. GUNNING, R. KRALOVICS, M. HERLING, M. MULLER, T. RULICKE, V. SEXL and R. MORIGGL. High activation of STAT5A drives peripheral T-cell lymphoma and leukemia. \textit{Haematologica}. PAVIA: FERRATA STORTI FOUNDATION, 2020, vol.~105, No~2, p.~435-447. ISSN~0390-6078. Available from: https://dx.doi.org/10.3324/haematol.2019.216986.

Detailed Information on Publication Record