ATRX In-Frame Fusion Neuroblastoma Is Sensitive to EZH2 Inhibition via Modulation of Neuronal Gene Signatures

Zulekha A. Qadeer; David Valle-Garcia; Dan Hasson; Zhen Sun; April Cook; Christie Nguyen; Aroa Soriano; Anqi Ma; Lyra M. Griffiths; Maged Zeineldin; Dan Filipescu; Luz Jubierre; Asif Chowdhury; Orla Deevy; Xiang Chen; David B. Finkelstein; Armita Bahrami; Elizabeth Stewart; Sara Federico; Soledad Gallego; Fumiko Dekio; Mary Fowkes; David Meni; John M. Maris; William A. Weiss; Stephen S. Roberts; Nai Kong V. Cheung; Jian Jin; Miguel F. Segura; Michael A. Dyer; Emily Bernstein

doi:10.1016/j.ccell.2019.09.002

ATRX In-Frame Fusion Neuroblastoma Is Sensitive to EZH2 Inhibition via Modulation of Neuronal Gene Signatures

Zulekha A. Qadeer, David Valle-Garcia, Dan Hasson, Zhen Sun, April Cook, Christie Nguyen, Aroa Soriano, Anqi Ma, Lyra M. Griffiths, Maged Zeineldin, Dan Filipescu, Luz Jubierre, Asif Chowdhury, Orla Deevy, Xiang Chen, David B. Finkelstein, Armita Bahrami, Elizabeth Stewart, Sara Federico, Soledad GallegoFumiko Dekio, Mary Fowkes, David Meni, John M. Maris, William A. Weiss, Stephen S. Roberts, Nai Kong V. Cheung, Jian Jin, Miguel F. Segura, Michael A. Dyer, Emily Bernstein

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

41 Scopus citations

Abstract

Qadeer et al. show that ATRX in-frame fusions (IFF), found in a subset of neuroblastomas, are redistributed from wild-type ATRX-binding sites to other genomic regions, including the REST promoter. REST expression silences neuronal differentiation genes, which can be derepressed with EZH2 inhibitors to suppress ATRX IFF cell growth.

Original language	English
Pages (from-to)	512-527.e9
Journal	Cancer Cell
Volume	36
Issue number	5
DOIs	https://doi.org/10.1016/j.ccell.2019.09.002
State	Published - 11 Nov 2019

Keywords

ATRX
EZH2
REST
epigenetic therapeutics
neuroblastoma
neuronal differentiation
tazemetostat

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10.1016/j.ccell.2019.09.002

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Qadeer, Z. A., Valle-Garcia, D., Hasson, D., Sun, Z., Cook, A., Nguyen, C., Soriano, A., Ma, A., Griffiths, L. M., Zeineldin, M., Filipescu, D., Jubierre, L., Chowdhury, A., Deevy, O., Chen, X., Finkelstein, D. B., Bahrami, A., Stewart, E., Federico, S., ... Bernstein, E. (2019). ATRX In-Frame Fusion Neuroblastoma Is Sensitive to EZH2 Inhibition via Modulation of Neuronal Gene Signatures. Cancer Cell, 36(5), 512-527.e9. https://doi.org/10.1016/j.ccell.2019.09.002

@article{6bf14198454344e39f285a483bd4df5a,

title = "ATRX In-Frame Fusion Neuroblastoma Is Sensitive to EZH2 Inhibition via Modulation of Neuronal Gene Signatures",

abstract = "Qadeer et al. show that ATRX in-frame fusions (IFF), found in a subset of neuroblastomas, are redistributed from wild-type ATRX-binding sites to other genomic regions, including the REST promoter. REST expression silences neuronal differentiation genes, which can be derepressed with EZH2 inhibitors to suppress ATRX IFF cell growth.",

keywords = "ATRX, EZH2, REST, epigenetic therapeutics, neuroblastoma, neuronal differentiation, tazemetostat",

author = "Qadeer, {Zulekha A.} and David Valle-Garcia and Dan Hasson and Zhen Sun and April Cook and Christie Nguyen and Aroa Soriano and Anqi Ma and Griffiths, {Lyra M.} and Maged Zeineldin and Dan Filipescu and Luz Jubierre and Asif Chowdhury and Orla Deevy and Xiang Chen and Finkelstein, {David B.} and Armita Bahrami and Elizabeth Stewart and Sara Federico and Soledad Gallego and Fumiko Dekio and Mary Fowkes and David Meni and Maris, {John M.} and Weiss, {William A.} and Roberts, {Stephen S.} and Cheung, {Nai Kong V.} and Jian Jin and Segura, {Miguel F.} and Dyer, {Michael A.} and Emily Bernstein",

note = "Funding Information: On behalf of Emily Bernstein, Zulekha A. Qadeer, and Dan Hasson, the Icahn School of Medicine at Mount Sinai has filed a patent application covering the subject matter of this research. N.-K.V.C. reports receiving commercial research grants from Y-mAbs Therapeutics and Abpro-Labs ; holding ownership interest/equity in Y-mAbs Therapeutics, holding ownership interest/equity in Abpro-Labs, and owning stock options in Eureka Therapeutics. N.-K.V.C. is the inventor and owner of issued patents licensed by Memorial Sloan Kettering to Y-mAbs Therapeutics, Biotec Pharmacon, and Abpro-Labs. Hu3F8 and 8H9 were licensed by Memorial Sloan Kettering Cancer Center (MSKCC) to Y-mAbs Therapeutics. Both MSKCC and N.-K.V.C. have financial interest in Y-mAbs. N.-K.V.C. is an advisory board member for Abpro-Labs and Eureka Therapeutics. The other authors declare no competing interests. Funding Information: The authors thank Idan Cohen, Rana Elkholi, Avi Ma'ayan, Matthew O'Connell, Ziyang Zhang, and current and former members of the E.B., R. Parsons, N. Jabado, and W.A.W. laboratories for advice, reagents, and technical support. We thank the ISMMS Genomics Core Facility, ISMMS Department of Oncological Sciences Sequencing Facility, Scientific Computing at ISMMS, Office of Research Infrastructure of the NIH to ISMMS (S10OD018522), St. Jude Hartwell Center, and St. Jude Department of Computational Biology. Bioinformatics analysis was assisted with the Bridges system (NSF award ACI-1445606) at the Pittsburgh Supercomputing Center through the Extreme Science and Engineering Discovery Environment (XSEDE) ( NSF grant ACI-1548562 ). This work was supported by the NCI T32CA078207-11 , DOD PRCRP Horizon award CA150773, and an NCI T32CA151022-07 to Z.A.Q., Instituto de Salud Carlos III ( CPII16/00006 and PI14/00561 , co-financed by the European Regional Development Fund ) and European Commission's Framework Program 7 ( Marie Curie Career Integration Grants ) to M.F.S., NIH R01 CA124709 to J.M.M., NIH R01 GM122749 to J.J., Cycle for Survival and Kylie Rowand Foundation to S.S.R., and Catie Hoch Foundation grant to N.-K.V.C. This work was supported, in part, by Cancer Center Support P30 CA21765 to St. Jude Children's Research Hospital , grants to M.A.D. from the NIH ( EY014867 , EY018599 , and CA168875 ), American Lebanese Syrian Associated Charities , Alex{\textquoteright}s Lemonade Stand Foundation , Tully Family Foundation , Passano Foundation , and HHMI . This work was supported by the Tisch Cancer Institute P30 CA196521 , a Developmental Research Pilot Project Program ( ISMMS ), and St. Baldrick's Foundation to E.B. Funding Information: The authors thank Idan Cohen, Rana Elkholi, Avi Ma'ayan, Matthew O'Connell, Ziyang Zhang, and current and former members of the E.B. R. Parsons, N. Jabado, and W.A.W. laboratories for advice, reagents, and technical support. We thank the ISMMS Genomics Core Facility, ISMMS Department of Oncological Sciences Sequencing Facility, Scientific Computing at ISMMS, Office of Research Infrastructure of the NIH to ISMMS (S10OD018522), St. Jude Hartwell Center, and St. Jude Department of Computational Biology. Bioinformatics analysis was assisted with the Bridges system (NSF award ACI-1445606) at the Pittsburgh Supercomputing Center through the Extreme Science and Engineering Discovery Environment (XSEDE) (NSF grant ACI-1548562). This work was supported by the NCI T32CA078207-11, DOD PRCRP Horizon award CA150773, and an NCI T32CA151022-07 to Z.A.Q. Instituto de Salud Carlos III (CPII16/00006 and PI14/00561, co-financed by the European Regional Development Fund) and European Commission's Framework Program 7 (Marie Curie Career Integration Grants) to M.F.S. NIH R01 CA124709 to J.M.M. NIH R01 GM122749 to J.J. Cycle for Survival and Kylie Rowand Foundation to S.S.R. and Catie Hoch Foundation grant to N.-K.V.C. This work was supported, in part, by Cancer Center Support P30 CA21765 to St. Jude Children's Research Hospital, grants to M.A.D. from the NIH (EY014867, EY018599, and CA168875), American Lebanese Syrian Associated Charities, Alex's Lemonade Stand Foundation, Tully Family Foundation, Passano Foundation, and HHMI. This work was supported by the Tisch Cancer Institute P30 CA196521, a Developmental Research Pilot Project Program (ISMMS), and St. Baldrick's Foundation to E.B. Conceptualization, Z.A.Q. and E.B.; Methodology, Z.A.Q. D.V.-G. D.H. Z.S. A. Cook, C.N. L.M.G. M.Z. D.F. A.B. M.F.S. M.A.D. and E.B.; Investigation, Z.A.Q. D.V.-G. D.H. Z.S. A. Cook, C.N. A.S. L.M.G. M.Z. L.J. D.F. A. Chowdhury, X.C. D.B.F. A.B. and E.S.; Formal Analysis, Z.A.Q. D.V.-G. D.H. C.N. X.C. D.B.F. A.B. F.D. and M.F.; Validation, O.D. and E.S.; Resources, A.M. D.M. E.S. S.F. S.G. J.M.M. S.S.R. N.-K.V.C. W.A.W. J.J. M.F.S. M.A.D. and E.B.; Data Curation, L.M.G.; Writing – Original Draft, Z.A.Q. and E.B.; Writing – Review & Editing, Z.A.Q. D.V.-G. D.H. Z.S. A. Cook, C.N. W.A.W. and E.B.; Funding Acquisition, W.A.W. J.J. M.F.S. M.A.D. and E.B.; Supervision, J.J. M.F.S. M.A.D. and E.B. On behalf of Emily Bernstein, Zulekha A. Qadeer, and Dan Hasson, the Icahn School of Medicine at Mount Sinai has filed a patent application covering the subject matter of this research. N.-K.V.C. reports receiving commercial research grants from Y-mAbs Therapeutics and Abpro-Labs; holding ownership interest/equity in Y-mAbs Therapeutics, holding ownership interest/equity in Abpro-Labs, and owning stock options in Eureka Therapeutics. N.-K.V.C. is the inventor and owner of issued patents licensed by Memorial Sloan Kettering to Y-mAbs Therapeutics, Biotec Pharmacon, and Abpro-Labs. Hu3F8 and 8H9 were licensed by Memorial Sloan Kettering Cancer Center (MSKCC) to Y-mAbs Therapeutics. Both MSKCC and N.-K.V.C. have financial interest in Y-mAbs. N.-K.V.C. is an advisory board member for Abpro-Labs and Eureka Therapeutics. The other authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

year = "2019",

month = nov,

day = "11",

doi = "10.1016/j.ccell.2019.09.002",

language = "English",

volume = "36",

pages = "512--527.e9",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "5",

}

Qadeer, ZA, Valle-Garcia, D, Hasson, D, Sun, Z, Cook, A, Nguyen, C, Soriano, A, Ma, A, Griffiths, LM, Zeineldin, M, Filipescu, D, Jubierre, L, Chowdhury, A, Deevy, O, Chen, X, Finkelstein, DB, Bahrami, A, Stewart, E, Federico, S, Gallego, S, Dekio, F, Fowkes, M, Meni, D, Maris, JM, Weiss, WA, Roberts, SS, Cheung, NKV, Jin, J, Segura, MF, Dyer, MA & Bernstein, E 2019, 'ATRX In-Frame Fusion Neuroblastoma Is Sensitive to EZH2 Inhibition via Modulation of Neuronal Gene Signatures', Cancer Cell, vol. 36, no. 5, pp. 512-527.e9. https://doi.org/10.1016/j.ccell.2019.09.002

TY - JOUR

T1 - ATRX In-Frame Fusion Neuroblastoma Is Sensitive to EZH2 Inhibition via Modulation of Neuronal Gene Signatures

AU - Qadeer, Zulekha A.

AU - Valle-Garcia, David

AU - Hasson, Dan

AU - Sun, Zhen

AU - Cook, April

AU - Nguyen, Christie

AU - Soriano, Aroa

AU - Ma, Anqi

AU - Griffiths, Lyra M.

AU - Zeineldin, Maged

AU - Filipescu, Dan

AU - Jubierre, Luz

AU - Chowdhury, Asif

AU - Deevy, Orla

AU - Chen, Xiang

AU - Finkelstein, David B.

AU - Bahrami, Armita

AU - Stewart, Elizabeth

AU - Federico, Sara

AU - Gallego, Soledad

AU - Dekio, Fumiko

AU - Fowkes, Mary

AU - Meni, David

AU - Maris, John M.

AU - Weiss, William A.

AU - Roberts, Stephen S.

AU - Cheung, Nai Kong V.

AU - Jin, Jian

AU - Segura, Miguel F.

AU - Dyer, Michael A.

AU - Bernstein, Emily

N1 - Funding Information: On behalf of Emily Bernstein, Zulekha A. Qadeer, and Dan Hasson, the Icahn School of Medicine at Mount Sinai has filed a patent application covering the subject matter of this research. N.-K.V.C. reports receiving commercial research grants from Y-mAbs Therapeutics and Abpro-Labs ; holding ownership interest/equity in Y-mAbs Therapeutics, holding ownership interest/equity in Abpro-Labs, and owning stock options in Eureka Therapeutics. N.-K.V.C. is the inventor and owner of issued patents licensed by Memorial Sloan Kettering to Y-mAbs Therapeutics, Biotec Pharmacon, and Abpro-Labs. Hu3F8 and 8H9 were licensed by Memorial Sloan Kettering Cancer Center (MSKCC) to Y-mAbs Therapeutics. Both MSKCC and N.-K.V.C. have financial interest in Y-mAbs. N.-K.V.C. is an advisory board member for Abpro-Labs and Eureka Therapeutics. The other authors declare no competing interests. Funding Information: The authors thank Idan Cohen, Rana Elkholi, Avi Ma'ayan, Matthew O'Connell, Ziyang Zhang, and current and former members of the E.B., R. Parsons, N. Jabado, and W.A.W. laboratories for advice, reagents, and technical support. We thank the ISMMS Genomics Core Facility, ISMMS Department of Oncological Sciences Sequencing Facility, Scientific Computing at ISMMS, Office of Research Infrastructure of the NIH to ISMMS (S10OD018522), St. Jude Hartwell Center, and St. Jude Department of Computational Biology. Bioinformatics analysis was assisted with the Bridges system (NSF award ACI-1445606) at the Pittsburgh Supercomputing Center through the Extreme Science and Engineering Discovery Environment (XSEDE) ( NSF grant ACI-1548562 ). This work was supported by the NCI T32CA078207-11 , DOD PRCRP Horizon award CA150773, and an NCI T32CA151022-07 to Z.A.Q., Instituto de Salud Carlos III ( CPII16/00006 and PI14/00561 , co-financed by the European Regional Development Fund ) and European Commission's Framework Program 7 ( Marie Curie Career Integration Grants ) to M.F.S., NIH R01 CA124709 to J.M.M., NIH R01 GM122749 to J.J., Cycle for Survival and Kylie Rowand Foundation to S.S.R., and Catie Hoch Foundation grant to N.-K.V.C. This work was supported, in part, by Cancer Center Support P30 CA21765 to St. Jude Children's Research Hospital , grants to M.A.D. from the NIH ( EY014867 , EY018599 , and CA168875 ), American Lebanese Syrian Associated Charities , Alex’s Lemonade Stand Foundation , Tully Family Foundation , Passano Foundation , and HHMI . This work was supported by the Tisch Cancer Institute P30 CA196521 , a Developmental Research Pilot Project Program ( ISMMS ), and St. Baldrick's Foundation to E.B. Funding Information: The authors thank Idan Cohen, Rana Elkholi, Avi Ma'ayan, Matthew O'Connell, Ziyang Zhang, and current and former members of the E.B. R. Parsons, N. Jabado, and W.A.W. laboratories for advice, reagents, and technical support. We thank the ISMMS Genomics Core Facility, ISMMS Department of Oncological Sciences Sequencing Facility, Scientific Computing at ISMMS, Office of Research Infrastructure of the NIH to ISMMS (S10OD018522), St. Jude Hartwell Center, and St. Jude Department of Computational Biology. Bioinformatics analysis was assisted with the Bridges system (NSF award ACI-1445606) at the Pittsburgh Supercomputing Center through the Extreme Science and Engineering Discovery Environment (XSEDE) (NSF grant ACI-1548562). This work was supported by the NCI T32CA078207-11, DOD PRCRP Horizon award CA150773, and an NCI T32CA151022-07 to Z.A.Q. Instituto de Salud Carlos III (CPII16/00006 and PI14/00561, co-financed by the European Regional Development Fund) and European Commission's Framework Program 7 (Marie Curie Career Integration Grants) to M.F.S. NIH R01 CA124709 to J.M.M. NIH R01 GM122749 to J.J. Cycle for Survival and Kylie Rowand Foundation to S.S.R. and Catie Hoch Foundation grant to N.-K.V.C. This work was supported, in part, by Cancer Center Support P30 CA21765 to St. Jude Children's Research Hospital, grants to M.A.D. from the NIH (EY014867, EY018599, and CA168875), American Lebanese Syrian Associated Charities, Alex's Lemonade Stand Foundation, Tully Family Foundation, Passano Foundation, and HHMI. This work was supported by the Tisch Cancer Institute P30 CA196521, a Developmental Research Pilot Project Program (ISMMS), and St. Baldrick's Foundation to E.B. Conceptualization, Z.A.Q. and E.B.; Methodology, Z.A.Q. D.V.-G. D.H. Z.S. A. Cook, C.N. L.M.G. M.Z. D.F. A.B. M.F.S. M.A.D. and E.B.; Investigation, Z.A.Q. D.V.-G. D.H. Z.S. A. Cook, C.N. A.S. L.M.G. M.Z. L.J. D.F. A. Chowdhury, X.C. D.B.F. A.B. and E.S.; Formal Analysis, Z.A.Q. D.V.-G. D.H. C.N. X.C. D.B.F. A.B. F.D. and M.F.; Validation, O.D. and E.S.; Resources, A.M. D.M. E.S. S.F. S.G. J.M.M. S.S.R. N.-K.V.C. W.A.W. J.J. M.F.S. M.A.D. and E.B.; Data Curation, L.M.G.; Writing – Original Draft, Z.A.Q. and E.B.; Writing – Review & Editing, Z.A.Q. D.V.-G. D.H. Z.S. A. Cook, C.N. W.A.W. and E.B.; Funding Acquisition, W.A.W. J.J. M.F.S. M.A.D. and E.B.; Supervision, J.J. M.F.S. M.A.D. and E.B. On behalf of Emily Bernstein, Zulekha A. Qadeer, and Dan Hasson, the Icahn School of Medicine at Mount Sinai has filed a patent application covering the subject matter of this research. N.-K.V.C. reports receiving commercial research grants from Y-mAbs Therapeutics and Abpro-Labs; holding ownership interest/equity in Y-mAbs Therapeutics, holding ownership interest/equity in Abpro-Labs, and owning stock options in Eureka Therapeutics. N.-K.V.C. is the inventor and owner of issued patents licensed by Memorial Sloan Kettering to Y-mAbs Therapeutics, Biotec Pharmacon, and Abpro-Labs. Hu3F8 and 8H9 were licensed by Memorial Sloan Kettering Cancer Center (MSKCC) to Y-mAbs Therapeutics. Both MSKCC and N.-K.V.C. have financial interest in Y-mAbs. N.-K.V.C. is an advisory board member for Abpro-Labs and Eureka Therapeutics. The other authors declare no competing interests. Publisher Copyright: © 2019 Elsevier Inc.

PY - 2019/11/11

Y1 - 2019/11/11

N2 - Qadeer et al. show that ATRX in-frame fusions (IFF), found in a subset of neuroblastomas, are redistributed from wild-type ATRX-binding sites to other genomic regions, including the REST promoter. REST expression silences neuronal differentiation genes, which can be derepressed with EZH2 inhibitors to suppress ATRX IFF cell growth.

AB - Qadeer et al. show that ATRX in-frame fusions (IFF), found in a subset of neuroblastomas, are redistributed from wild-type ATRX-binding sites to other genomic regions, including the REST promoter. REST expression silences neuronal differentiation genes, which can be derepressed with EZH2 inhibitors to suppress ATRX IFF cell growth.

KW - ATRX

KW - EZH2

KW - REST

KW - epigenetic therapeutics

KW - neuroblastoma

KW - neuronal differentiation

KW - tazemetostat

UR - http://www.scopus.com/inward/record.url?scp=85074426501&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2019.09.002

DO - 10.1016/j.ccell.2019.09.002

M3 - Article

C2 - 31631027

AN - SCOPUS:85074426501

SN - 1535-6108

VL - 36

SP - 512-527.e9

JO - Cancer Cell

JF - Cancer Cell

IS - 5

ER -

ATRX In-Frame Fusion Neuroblastoma Is Sensitive to EZH2 Inhibition via Modulation of Neuronal Gene Signatures

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Keywords

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