Sox4 Is a Key Oncogenic Target in C/EBPα Mutant Acute Myeloid Leukemia

Hong Zhang; Meritxell Alberich-Jorda; Giovanni Amabile; Henry Yang; Philipp B. Staber; Annalisa DiRuscio; Robert S. Welner; Alexander Ebralidze; Junyan Zhang; Elena Levantini; Véronique Lefebvre; Peter J.M. Valk; Ruud Delwel; Maarten Hoogenkamp; Claus Nerlov; Jörg Cammenga; Borja Saez; David T. Scadden; Constanze Bonifer; Min Ye; Daniel G. Tenen

doi:10.1016/j.ccr.2013.09.018

Sox4 Is a Key Oncogenic Target in C/EBPα Mutant Acute Myeloid Leukemia

Hong Zhang
, Meritxell Alberich-Jorda
, Giovanni Amabile
, Henry Yang
, Philipp B. Staber
, Annalisa DiRuscio
, Robert S. Welner
, Alexander Ebralidze
, Junyan Zhang
, Elena Levantini
, Véronique Lefebvre
, Peter J.M. Valk
, Ruud Delwel
, Maarten Hoogenkamp
, Claus Nerlov
, Jörg Cammenga
, Borja Saez
, David T. Scadden
, Constanze Bonifer
, Min Ye

Daniel G. Tenen

Risultato della ricerca: Contributo su rivista › Articolo in rivista › peer review

Abstract

Mutation or epigenetic silencing of the transcription factor C/EBPα is observed in ~10% of patients with acute myeloid leukemia (AML). In both cases, a common global gene expression profile is observed, but downstream targets relevant for leukemogenesis are not known. Here, we identify Sox4 as a direct target of C/EBPα whereby its expression is inversely correlated with C/EBPα activity. Downregulation of Sox4 abrogated increased self-renewal of leukemic cells and restored their differentiation. Gene expression profiles of leukemia-initiating cells (LICs) from both Sox4 overexpression and murine C/EBPα mutant AML models clustered together but differed from other types of AML. Our data demonstrate that Sox4 overexpression resulting from C/EBPα inactivation contributes to the development of leukemia with a distinct LIC phenotype.

Lingua originale	Inglese
pagine (da-a)	575-588
Numero di pagine	14
Rivista	Cancer Cell
Volume	24
Numero di pubblicazione	5
DOI	https://doi.org/10.1016/j.ccr.2013.09.018
Stato di pubblicazione	Pubblicato - 11 nov 2013
Pubblicato esternamente	Sì

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10.1016/j.ccr.2013.09.018

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Zhang, H., Alberich-Jorda, M., Amabile, G., Yang, H., Staber, P. B., DiRuscio, A., Welner, R. S., Ebralidze, A., Zhang, J., Levantini, E., Lefebvre, V., Valk, P. J. M., Delwel, R., Hoogenkamp, M., Nerlov, C., Cammenga, J., Saez, B., Scadden, D. T., Bonifer, C., ... Tenen, D. G. (2013). Sox4 Is a Key Oncogenic Target in C/EBPα Mutant Acute Myeloid Leukemia. Cancer Cell, 24(5), 575-588. https://doi.org/10.1016/j.ccr.2013.09.018

@article{481ad4a03c5d4f55b33b6a327703f1fd,

title = "Sox4 Is a Key Oncogenic Target in C/EBPα Mutant Acute Myeloid Leukemia",

abstract = "Mutation or epigenetic silencing of the transcription factor C/EBPα is observed in \textasciitilde{}10\% of patients with acute myeloid leukemia (AML). In both cases, a common global gene expression profile is observed, but downstream targets relevant for leukemogenesis are not known. Here, we identify Sox4 as a direct target of C/EBPα whereby its expression is inversely correlated with C/EBPα activity. Downregulation of Sox4 abrogated increased self-renewal of leukemic cells and restored their differentiation. Gene expression profiles of leukemia-initiating cells (LICs) from both Sox4 overexpression and murine C/EBPα mutant AML models clustered together but differed from other types of AML. Our data demonstrate that Sox4 overexpression resulting from C/EBPα inactivation contributes to the development of leukemia with a distinct LIC phenotype.",

author = "Hong Zhang and Meritxell Alberich-Jorda and Giovanni Amabile and Henry Yang and Staber, \{Philipp B.\} and Annalisa DiRuscio and Welner, \{Robert S.\} and Alexander Ebralidze and Junyan Zhang and Elena Levantini and V{\'e}ronique Lefebvre and Valk, \{Peter J.M.\} and Ruud Delwel and Maarten Hoogenkamp and Claus Nerlov and J{\"o}rg Cammenga and Borja Saez and Scadden, \{David T.\} and Constanze Bonifer and Min Ye and Tenen, \{Daniel G.\}",

note = "Funding Information: This study was supported by National Institutes of Health grants HL 56745 and CA118316 and Harvard Stem Cell Institute grant DP-0086-10-00. M.A. was supported by Navrat grant LK21307 from the Czech Ministry of Youth, Health and Sports. G.A. was supported by a Collegio Ghislieri fellowship. P.S. was supported by the Austrian Research Foundation and European Union. A.D.R. was supported by the Societa{\textquoteright} Italiana di Ematologia Sperimentale borsa di studio “Dr. Tito Bastianello.” R.S.W. was supported by the Jose Carreras Leukemia Foundation (FIJC F11/01). E.L. was supported by FAMRI CIA. V.L. was supported by National Institutes of Health grant NIH/NIAMS R01 AR54153. C.B. and M.H. were supported by grants from Leukaemia Lymphoma Research. We thank all members of the Tenen laboratory and Kristian Reckzeh for helpful discussions, the Harvard Stem Cell Institute/Beth Israel Deaconess Medical Center Flow Cytometry Core for their expertise, Angie Tan Lay Keng and Lee Ming Hui from the NUS-Duke genomic facility in Singapore for their expertise in microarray analysis, and Archibald Perkins and Joseph R. Nevins for providing us with experimental reagents. ",

year = "2013",

month = nov,

day = "11",

doi = "10.1016/j.ccr.2013.09.018",

language = "English",

volume = "24",

pages = "575--588",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "5",

}

Zhang, H, Alberich-Jorda, M, Amabile, G, Yang, H, Staber, PB, DiRuscio, A, Welner, RS, Ebralidze, A, Zhang, J, Levantini, E, Lefebvre, V, Valk, PJM, Delwel, R, Hoogenkamp, M, Nerlov, C, Cammenga, J, Saez, B, Scadden, DT, Bonifer, C, Ye, M & Tenen, DG 2013, 'Sox4 Is a Key Oncogenic Target in C/EBPα Mutant Acute Myeloid Leukemia', Cancer Cell, vol. 24, n. 5, pagg. 575-588. https://doi.org/10.1016/j.ccr.2013.09.018

TY - JOUR

T1 - Sox4 Is a Key Oncogenic Target in C/EBPα Mutant Acute Myeloid Leukemia

AU - Zhang, Hong

AU - Alberich-Jorda, Meritxell

AU - Amabile, Giovanni

AU - Yang, Henry

AU - Staber, Philipp B.

AU - DiRuscio, Annalisa

AU - Welner, Robert S.

AU - Ebralidze, Alexander

AU - Zhang, Junyan

AU - Levantini, Elena

AU - Lefebvre, Véronique

AU - Valk, Peter J.M.

AU - Delwel, Ruud

AU - Hoogenkamp, Maarten

AU - Nerlov, Claus

AU - Cammenga, Jörg

AU - Saez, Borja

AU - Scadden, David T.

AU - Bonifer, Constanze

AU - Ye, Min

AU - Tenen, Daniel G.

N1 - Funding Information: This study was supported by National Institutes of Health grants HL 56745 and CA118316 and Harvard Stem Cell Institute grant DP-0086-10-00. M.A. was supported by Navrat grant LK21307 from the Czech Ministry of Youth, Health and Sports. G.A. was supported by a Collegio Ghislieri fellowship. P.S. was supported by the Austrian Research Foundation and European Union. A.D.R. was supported by the Societa’ Italiana di Ematologia Sperimentale borsa di studio “Dr. Tito Bastianello.” R.S.W. was supported by the Jose Carreras Leukemia Foundation (FIJC F11/01). E.L. was supported by FAMRI CIA. V.L. was supported by National Institutes of Health grant NIH/NIAMS R01 AR54153. C.B. and M.H. were supported by grants from Leukaemia Lymphoma Research. We thank all members of the Tenen laboratory and Kristian Reckzeh for helpful discussions, the Harvard Stem Cell Institute/Beth Israel Deaconess Medical Center Flow Cytometry Core for their expertise, Angie Tan Lay Keng and Lee Ming Hui from the NUS-Duke genomic facility in Singapore for their expertise in microarray analysis, and Archibald Perkins and Joseph R. Nevins for providing us with experimental reagents.

PY - 2013/11/11

Y1 - 2013/11/11

N2 - Mutation or epigenetic silencing of the transcription factor C/EBPα is observed in ~10% of patients with acute myeloid leukemia (AML). In both cases, a common global gene expression profile is observed, but downstream targets relevant for leukemogenesis are not known. Here, we identify Sox4 as a direct target of C/EBPα whereby its expression is inversely correlated with C/EBPα activity. Downregulation of Sox4 abrogated increased self-renewal of leukemic cells and restored their differentiation. Gene expression profiles of leukemia-initiating cells (LICs) from both Sox4 overexpression and murine C/EBPα mutant AML models clustered together but differed from other types of AML. Our data demonstrate that Sox4 overexpression resulting from C/EBPα inactivation contributes to the development of leukemia with a distinct LIC phenotype.

AB - Mutation or epigenetic silencing of the transcription factor C/EBPα is observed in ~10% of patients with acute myeloid leukemia (AML). In both cases, a common global gene expression profile is observed, but downstream targets relevant for leukemogenesis are not known. Here, we identify Sox4 as a direct target of C/EBPα whereby its expression is inversely correlated with C/EBPα activity. Downregulation of Sox4 abrogated increased self-renewal of leukemic cells and restored their differentiation. Gene expression profiles of leukemia-initiating cells (LICs) from both Sox4 overexpression and murine C/EBPα mutant AML models clustered together but differed from other types of AML. Our data demonstrate that Sox4 overexpression resulting from C/EBPα inactivation contributes to the development of leukemia with a distinct LIC phenotype.

UR - https://www.scopus.com/pages/publications/84887553701

U2 - 10.1016/j.ccr.2013.09.018

DO - 10.1016/j.ccr.2013.09.018

M3 - Article

SN - 1535-6108

VL - 24

SP - 575

EP - 588

JO - Cancer Cell

JF - Cancer Cell

IS - 5

ER -

Sox4 Is a Key Oncogenic Target in C/EBPα Mutant Acute Myeloid Leukemia

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