Increased survival and cell cycle progression pathways are required for EWS/FLI1-induced malignant transformation

Tahereh Javaheri; Zahra Kazemi; Jan Pencik; Ha Tt Pham; Maximilian Kauer; Rahil Noorizadeh; Barbara Sax; Harini Nivarthi; Michaela Schlederer; Barbara Maurer; Maximillian Hofbauer; Dave Nt Aryee; Marc Wiedner; Eleni M. Tomazou; Malcolm Logan; Christine Hartmann; Jan P. Tuckermann; Lukas Kenner; Mario Mikula; Helmut Dolznig; Aykut Üren; Günther H. Richter; Florian Grebien; Heinrich Kovar; Richard Moriggl

doi:10.1038/cddis.2016.268

Increased survival and cell cycle progression pathways are required for EWS/FLI1-induced malignant transformation

Tahereh Javaheri, Zahra Kazemi, Jan Pencik, Ha Tt Pham, Maximilian Kauer, Rahil Noorizadeh, Barbara Sax, Harini Nivarthi, Michaela Schlederer, Barbara Maurer, Maximillian Hofbauer, Dave Nt Aryee, Marc Wiedner, Eleni M. Tomazou, Malcolm Logan, Christine Hartmann, Jan P. Tuckermann, Lukas Kenner, Mario Mikula, Helmut DolznigAykut Üren, Günther H. Richter, Florian Grebien, Heinrich Kovar, Richard Moriggl

Research output: Contribution to journal › Article › peer-review

16 Citations (Scopus)

170 Downloads (Pure)

Abstract

Ewing sarcoma (ES) is the second most frequent childhood bone cancer driven by the EWS/FLI1 (EF) fusion protein. Genetically defined ES models are needed to understand how EF expression changes bone precursor cell differentiation, how ES arises and through which mechanisms of inhibition it can be targeted. We used mesenchymal Prx1-directed conditional EF expression in mice to study bone development and to establish a reliable sarcoma model. EF expression arrested early chondrocyte and osteoblast differentiation due to changed signaling pathways such as hedgehog, WNT or growth factor signaling. Mesenchymal stem cells (MSCs) expressing EF showed high self-renewal capacity and maintained an undifferentiated state despite high apoptosis. Blocking apoptosis through enforced BCL2 family member expression in MSCs promoted efficient and rapid sarcoma formation when transplanted to immunocompromised mice. Mechanistically, high BCL2 family member and CDK4, but low P53 and INK4A protein expression synergized in Ewing-like sarcoma development. Functionally, knockdown of Mcl1 or Cdk4 or their combined pharmacologic inhibition resulted in growth arrest and apoptosis in both established human ES cell lines and EF-transformed mouse MSCs. Combinatorial targeting of survival and cell cycle progression pathways could counteract this aggressive childhood cancer.

Original language	English
Article number	e2419
Number of pages	13
Journal	Cell Death & Disease
Volume	7
Issue number	10
Early online date	13 Oct 2016
DOIs	https://doi.org/10.1038/cddis.2016.268
Publication status	E-pub ahead of print - 13 Oct 2016

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/cddis.2016.268Licence: CC BY

Increased survival and cell_JAVAHERI_Accepted13October2016_GOLD VoR (CC BY)Final published version, 7.66 MBLicence: CC BY

Cite this

Javaheri, T., Kazemi, Z., Pencik, J., Pham, H. T., Kauer, M., Noorizadeh, R., Sax, B., Nivarthi, H., Schlederer, M., Maurer, B., Hofbauer, M., Aryee, D. N., Wiedner, M., Tomazou, E. M., Logan, M., Hartmann, C., Tuckermann, J. P., Kenner, L., Mikula, M., ... Moriggl, R. (2016). Increased survival and cell cycle progression pathways are required for EWS/FLI1-induced malignant transformation. Cell Death & Disease, 7(10), Article e2419. Advance online publication. https://doi.org/10.1038/cddis.2016.268

@article{90aece6391844e81afaa3e26e0af9fa3,

title = "Increased survival and cell cycle progression pathways are required for EWS/FLI1-induced malignant transformation",

abstract = "Ewing sarcoma (ES) is the second most frequent childhood bone cancer driven by the EWS/FLI1 (EF) fusion protein. Genetically defined ES models are needed to understand how EF expression changes bone precursor cell differentiation, how ES arises and through which mechanisms of inhibition it can be targeted. We used mesenchymal Prx1-directed conditional EF expression in mice to study bone development and to establish a reliable sarcoma model. EF expression arrested early chondrocyte and osteoblast differentiation due to changed signaling pathways such as hedgehog, WNT or growth factor signaling. Mesenchymal stem cells (MSCs) expressing EF showed high self-renewal capacity and maintained an undifferentiated state despite high apoptosis. Blocking apoptosis through enforced BCL2 family member expression in MSCs promoted efficient and rapid sarcoma formation when transplanted to immunocompromised mice. Mechanistically, high BCL2 family member and CDK4, but low P53 and INK4A protein expression synergized in Ewing-like sarcoma development. Functionally, knockdown of Mcl1 or Cdk4 or their combined pharmacologic inhibition resulted in growth arrest and apoptosis in both established human ES cell lines and EF-transformed mouse MSCs. Combinatorial targeting of survival and cell cycle progression pathways could counteract this aggressive childhood cancer.",

author = "Tahereh Javaheri and Zahra Kazemi and Jan Pencik and Pham, {Ha Tt} and Maximilian Kauer and Rahil Noorizadeh and Barbara Sax and Harini Nivarthi and Michaela Schlederer and Barbara Maurer and Maximillian Hofbauer and Aryee, {Dave Nt} and Marc Wiedner and Tomazou, {Eleni M.} and Malcolm Logan and Christine Hartmann and Tuckermann, {Jan P.} and Lukas Kenner and Mario Mikula and Helmut Dolznig and Aykut {\"U}ren and Richter, {G{\"u}nther H.} and Florian Grebien and Heinrich Kovar and Richard Moriggl",

year = "2016",

month = oct,

day = "13",

doi = "10.1038/cddis.2016.268",

language = "English",

volume = "7",

journal = "Cell Death & Disease",

issn = "2041-4889",

publisher = "Nature Publishing Group",

number = "10",

}

Javaheri, T, Kazemi, Z, Pencik, J, Pham, HT, Kauer, M, Noorizadeh, R, Sax, B, Nivarthi, H, Schlederer, M, Maurer, B, Hofbauer, M, Aryee, DN, Wiedner, M, Tomazou, EM, Logan, M, Hartmann, C, Tuckermann, JP, Kenner, L, Mikula, M, Dolznig, H, Üren, A, Richter, GH, Grebien, F, Kovar, H & Moriggl, R 2016, 'Increased survival and cell cycle progression pathways are required for EWS/FLI1-induced malignant transformation', Cell Death & Disease, vol. 7, no. 10, e2419. https://doi.org/10.1038/cddis.2016.268

TY - JOUR

T1 - Increased survival and cell cycle progression pathways are required for EWS/FLI1-induced malignant transformation

AU - Javaheri, Tahereh

AU - Kazemi, Zahra

AU - Pencik, Jan

AU - Pham, Ha Tt

AU - Kauer, Maximilian

AU - Noorizadeh, Rahil

AU - Sax, Barbara

AU - Nivarthi, Harini

AU - Schlederer, Michaela

AU - Maurer, Barbara

AU - Hofbauer, Maximillian

AU - Aryee, Dave Nt

AU - Wiedner, Marc

AU - Tomazou, Eleni M.

AU - Logan, Malcolm

AU - Hartmann, Christine

AU - Tuckermann, Jan P.

AU - Kenner, Lukas

AU - Mikula, Mario

AU - Dolznig, Helmut

AU - Üren, Aykut

AU - Richter, Günther H.

AU - Grebien, Florian

AU - Kovar, Heinrich

AU - Moriggl, Richard

PY - 2016/10/13

Y1 - 2016/10/13

N2 - Ewing sarcoma (ES) is the second most frequent childhood bone cancer driven by the EWS/FLI1 (EF) fusion protein. Genetically defined ES models are needed to understand how EF expression changes bone precursor cell differentiation, how ES arises and through which mechanisms of inhibition it can be targeted. We used mesenchymal Prx1-directed conditional EF expression in mice to study bone development and to establish a reliable sarcoma model. EF expression arrested early chondrocyte and osteoblast differentiation due to changed signaling pathways such as hedgehog, WNT or growth factor signaling. Mesenchymal stem cells (MSCs) expressing EF showed high self-renewal capacity and maintained an undifferentiated state despite high apoptosis. Blocking apoptosis through enforced BCL2 family member expression in MSCs promoted efficient and rapid sarcoma formation when transplanted to immunocompromised mice. Mechanistically, high BCL2 family member and CDK4, but low P53 and INK4A protein expression synergized in Ewing-like sarcoma development. Functionally, knockdown of Mcl1 or Cdk4 or their combined pharmacologic inhibition resulted in growth arrest and apoptosis in both established human ES cell lines and EF-transformed mouse MSCs. Combinatorial targeting of survival and cell cycle progression pathways could counteract this aggressive childhood cancer.

AB - Ewing sarcoma (ES) is the second most frequent childhood bone cancer driven by the EWS/FLI1 (EF) fusion protein. Genetically defined ES models are needed to understand how EF expression changes bone precursor cell differentiation, how ES arises and through which mechanisms of inhibition it can be targeted. We used mesenchymal Prx1-directed conditional EF expression in mice to study bone development and to establish a reliable sarcoma model. EF expression arrested early chondrocyte and osteoblast differentiation due to changed signaling pathways such as hedgehog, WNT or growth factor signaling. Mesenchymal stem cells (MSCs) expressing EF showed high self-renewal capacity and maintained an undifferentiated state despite high apoptosis. Blocking apoptosis through enforced BCL2 family member expression in MSCs promoted efficient and rapid sarcoma formation when transplanted to immunocompromised mice. Mechanistically, high BCL2 family member and CDK4, but low P53 and INK4A protein expression synergized in Ewing-like sarcoma development. Functionally, knockdown of Mcl1 or Cdk4 or their combined pharmacologic inhibition resulted in growth arrest and apoptosis in both established human ES cell lines and EF-transformed mouse MSCs. Combinatorial targeting of survival and cell cycle progression pathways could counteract this aggressive childhood cancer.

UR - http://www.scopus.com/inward/record.url?scp=85008719014&partnerID=8YFLogxK

U2 - 10.1038/cddis.2016.268

DO - 10.1038/cddis.2016.268

M3 - Article

C2 - 27735950

AN - SCOPUS:85008719014

SN - 2041-4889

VL - 7

JO - Cell Death & Disease

JF - Cell Death & Disease

IS - 10

M1 - e2419

ER -

Increased survival and cell cycle progression pathways are required for EWS/FLI1-induced malignant transformation

Abstract

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this