ETO2-GLIS2 Hijacks Transcriptional Complexes to Drive Cellular Identity and Self-Renewal in Pediatric Acute Megakaryoblastic Leukemia

Cécile Thirant, Cathy Ignacimouttou, Cécile K. Lopez, M'Boyba Diop, Lou Le Mouël, Clarisse Thiollier, Aurélie Siret, Phillipe Dessen, Zakia Aid, Julie Rivière, Philippe Rameau, Céline Lefebvre, Mehdi Khaled, Guy Leverger, Paola Ballerini, Arnaud Petit, Hana Raslova, Catherine L. Carmichael, Benjamin T. Kile, Eric Soler & 10 others John D. Crispino, Christian Wichmann, Françoise Pflumio, Jürg Schwaller, William Vainchenker, Camille Lobry, Nathalie Droin, Olivier A. Bernard, Sébastien Malinge, Thomas Mercher

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Chimeric transcription factors are a hallmark of human leukemia, but the molecular mechanisms by which they block differentiation and promote aberrant self-renewal remain unclear. Here, we demonstrate that the ETO2-GLIS2 fusion oncoprotein, which is found in aggressive acute megakaryoblastic leukemia, confers megakaryocytic identity via the GLIS2 moiety while both ETO2 and GLIS2 domains are required to drive increased self-renewal properties. ETO2-GLIS2 directly binds DNA to control transcription of associated genes by upregulation of expression and interaction with the ETS-related ERG protein at enhancer elements. Importantly, specific interference with ETO2-GLIS2 oligomerization reverses the transcriptional activation at enhancers and promotes megakaryocytic differentiation, providing a relevant interface to target in this poor-prognosis pediatric leukemia.

Original languageEnglish
Pages (from-to)452-465
Number of pages14
JournalCancer Cell
Volume31
Issue number3
DOIs
Publication statusPublished - 13 Mar 2017
Externally publishedYes

Keywords

  • AMKL
  • CBFA2T3
  • ChIP
  • CRISPR
  • enhancer
  • ERG
  • GLIS
  • leukemia
  • pediatric
  • transcription factor

Cite this

Thirant, C., Ignacimouttou, C., Lopez, C. K., Diop, MB., Le Mouël, L., Thiollier, C., ... Mercher, T. (2017). ETO2-GLIS2 Hijacks Transcriptional Complexes to Drive Cellular Identity and Self-Renewal in Pediatric Acute Megakaryoblastic Leukemia. Cancer Cell, 31(3), 452-465. https://doi.org/10.1016/j.ccell.2017.02.006
Thirant, Cécile ; Ignacimouttou, Cathy ; Lopez, Cécile K. ; Diop, M'Boyba ; Le Mouël, Lou ; Thiollier, Clarisse ; Siret, Aurélie ; Dessen, Phillipe ; Aid, Zakia ; Rivière, Julie ; Rameau, Philippe ; Lefebvre, Céline ; Khaled, Mehdi ; Leverger, Guy ; Ballerini, Paola ; Petit, Arnaud ; Raslova, Hana ; Carmichael, Catherine L. ; Kile, Benjamin T. ; Soler, Eric ; Crispino, John D. ; Wichmann, Christian ; Pflumio, Françoise ; Schwaller, Jürg ; Vainchenker, William ; Lobry, Camille ; Droin, Nathalie ; Bernard, Olivier A. ; Malinge, Sébastien ; Mercher, Thomas. / ETO2-GLIS2 Hijacks Transcriptional Complexes to Drive Cellular Identity and Self-Renewal in Pediatric Acute Megakaryoblastic Leukemia. In: Cancer Cell. 2017 ; Vol. 31, No. 3. pp. 452-465.
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title = "ETO2-GLIS2 Hijacks Transcriptional Complexes to Drive Cellular Identity and Self-Renewal in Pediatric Acute Megakaryoblastic Leukemia",
abstract = "Chimeric transcription factors are a hallmark of human leukemia, but the molecular mechanisms by which they block differentiation and promote aberrant self-renewal remain unclear. Here, we demonstrate that the ETO2-GLIS2 fusion oncoprotein, which is found in aggressive acute megakaryoblastic leukemia, confers megakaryocytic identity via the GLIS2 moiety while both ETO2 and GLIS2 domains are required to drive increased self-renewal properties. ETO2-GLIS2 directly binds DNA to control transcription of associated genes by upregulation of expression and interaction with the ETS-related ERG protein at enhancer elements. Importantly, specific interference with ETO2-GLIS2 oligomerization reverses the transcriptional activation at enhancers and promotes megakaryocytic differentiation, providing a relevant interface to target in this poor-prognosis pediatric leukemia.",
keywords = "AMKL, CBFA2T3, ChIP, CRISPR, enhancer, ERG, GLIS, leukemia, pediatric, transcription factor",
author = "C{\'e}cile Thirant and Cathy Ignacimouttou and Lopez, {C{\'e}cile K.} and M'Boyba Diop and {Le Mou{\"e}l}, Lou and Clarisse Thiollier and Aur{\'e}lie Siret and Phillipe Dessen and Zakia Aid and Julie Rivi{\`e}re and Philippe Rameau and C{\'e}line Lefebvre and Mehdi Khaled and Guy Leverger and Paola Ballerini and Arnaud Petit and Hana Raslova and Carmichael, {Catherine L.} and Kile, {Benjamin T.} and Eric Soler and Crispino, {John D.} and Christian Wichmann and Fran{\cc}oise Pflumio and J{\"u}rg Schwaller and William Vainchenker and Camille Lobry and Nathalie Droin and Bernard, {Olivier A.} and S{\'e}bastien Malinge and Thomas Mercher",
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Thirant, C, Ignacimouttou, C, Lopez, CK, Diop, MB, Le Mouël, L, Thiollier, C, Siret, A, Dessen, P, Aid, Z, Rivière, J, Rameau, P, Lefebvre, C, Khaled, M, Leverger, G, Ballerini, P, Petit, A, Raslova, H, Carmichael, CL, Kile, BT, Soler, E, Crispino, JD, Wichmann, C, Pflumio, F, Schwaller, J, Vainchenker, W, Lobry, C, Droin, N, Bernard, OA, Malinge, S & Mercher, T 2017, 'ETO2-GLIS2 Hijacks Transcriptional Complexes to Drive Cellular Identity and Self-Renewal in Pediatric Acute Megakaryoblastic Leukemia' Cancer Cell, vol. 31, no. 3, pp. 452-465. https://doi.org/10.1016/j.ccell.2017.02.006

ETO2-GLIS2 Hijacks Transcriptional Complexes to Drive Cellular Identity and Self-Renewal in Pediatric Acute Megakaryoblastic Leukemia. / Thirant, Cécile; Ignacimouttou, Cathy; Lopez, Cécile K.; Diop, M'Boyba; Le Mouël, Lou; Thiollier, Clarisse; Siret, Aurélie; Dessen, Phillipe; Aid, Zakia; Rivière, Julie; Rameau, Philippe; Lefebvre, Céline; Khaled, Mehdi; Leverger, Guy; Ballerini, Paola; Petit, Arnaud; Raslova, Hana; Carmichael, Catherine L.; Kile, Benjamin T.; Soler, Eric; Crispino, John D.; Wichmann, Christian; Pflumio, Françoise; Schwaller, Jürg; Vainchenker, William; Lobry, Camille; Droin, Nathalie; Bernard, Olivier A.; Malinge, Sébastien; Mercher, Thomas.

In: Cancer Cell, Vol. 31, No. 3, 13.03.2017, p. 452-465.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - ETO2-GLIS2 Hijacks Transcriptional Complexes to Drive Cellular Identity and Self-Renewal in Pediatric Acute Megakaryoblastic Leukemia

AU - Thirant, Cécile

AU - Ignacimouttou, Cathy

AU - Lopez, Cécile K.

AU - Diop, M'Boyba

AU - Le Mouël, Lou

AU - Thiollier, Clarisse

AU - Siret, Aurélie

AU - Dessen, Phillipe

AU - Aid, Zakia

AU - Rivière, Julie

AU - Rameau, Philippe

AU - Lefebvre, Céline

AU - Khaled, Mehdi

AU - Leverger, Guy

AU - Ballerini, Paola

AU - Petit, Arnaud

AU - Raslova, Hana

AU - Carmichael, Catherine L.

AU - Kile, Benjamin T.

AU - Soler, Eric

AU - Crispino, John D.

AU - Wichmann, Christian

AU - Pflumio, Françoise

AU - Schwaller, Jürg

AU - Vainchenker, William

AU - Lobry, Camille

AU - Droin, Nathalie

AU - Bernard, Olivier A.

AU - Malinge, Sébastien

AU - Mercher, Thomas

PY - 2017/3/13

Y1 - 2017/3/13

N2 - Chimeric transcription factors are a hallmark of human leukemia, but the molecular mechanisms by which they block differentiation and promote aberrant self-renewal remain unclear. Here, we demonstrate that the ETO2-GLIS2 fusion oncoprotein, which is found in aggressive acute megakaryoblastic leukemia, confers megakaryocytic identity via the GLIS2 moiety while both ETO2 and GLIS2 domains are required to drive increased self-renewal properties. ETO2-GLIS2 directly binds DNA to control transcription of associated genes by upregulation of expression and interaction with the ETS-related ERG protein at enhancer elements. Importantly, specific interference with ETO2-GLIS2 oligomerization reverses the transcriptional activation at enhancers and promotes megakaryocytic differentiation, providing a relevant interface to target in this poor-prognosis pediatric leukemia.

AB - Chimeric transcription factors are a hallmark of human leukemia, but the molecular mechanisms by which they block differentiation and promote aberrant self-renewal remain unclear. Here, we demonstrate that the ETO2-GLIS2 fusion oncoprotein, which is found in aggressive acute megakaryoblastic leukemia, confers megakaryocytic identity via the GLIS2 moiety while both ETO2 and GLIS2 domains are required to drive increased self-renewal properties. ETO2-GLIS2 directly binds DNA to control transcription of associated genes by upregulation of expression and interaction with the ETS-related ERG protein at enhancer elements. Importantly, specific interference with ETO2-GLIS2 oligomerization reverses the transcriptional activation at enhancers and promotes megakaryocytic differentiation, providing a relevant interface to target in this poor-prognosis pediatric leukemia.

KW - AMKL

KW - CBFA2T3

KW - ChIP

KW - CRISPR

KW - enhancer

KW - ERG

KW - GLIS

KW - leukemia

KW - pediatric

KW - transcription factor

UR - http://www.scopus.com/inward/record.url?scp=85015051869&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2017.02.006

DO - 10.1016/j.ccell.2017.02.006

M3 - Article

VL - 31

SP - 452

EP - 465

JO - Cancer Cell

JF - Cancer Cell

SN - 1535-6108

IS - 3

ER -