Site- and allele-specific polycomb dysregulation in T-cell leukaemia

Jean Marc Navarro; Aurore Touzart; Lydie C. Pradel; Marie Loosveld; Myriam Koubi; Romain Fenouil; Sandrine Le Noir; Muhammad Ahmad Maqbool; Ester Morgado; Claude Gregoire; Sebastien Jaeger; Emilie Mamessier; Charles Pignon; Salima Hacein-Bey-Abina; Bernard Malissen; Marta Gut; Ivo G. Gut; Hervé Dombret; Elizabeth A. MacIntyre; Steven J. Howe; H. Bobby Gaspar; Adrian J. Thrasher; Norbert Ifrah; Dominique Payet-Bornet; Estelle Duprez; Jean Christophe Andrau; Vahid Asnafi; Bertrand Nadel

doi:10.1038/ncomms7094

Site- and allele-specific polycomb dysregulation in T-cell leukaemia

Jean Marc Navarro
, Aurore Touzart
, Lydie C. Pradel
, Marie Loosveld
, Myriam Koubi
, Romain Fenouil
, Sandrine Le Noir
, Muhammad Ahmad Maqbool
, Ester Morgado
, Claude Gregoire
, Sebastien Jaeger
, Emilie Mamessier
, Charles Pignon
, Salima Hacein-Bey-Abina
, Bernard Malissen
, Marta Gut
, Ivo G. Gut
, Hervé Dombret
, Elizabeth A. MacIntyre
, Steven J. Howe

H. Bobby Gaspar, Adrian J. Thrasher, Norbert Ifrah, Dominique Payet-Bornet, Estelle Duprez, Jean Christophe Andrau, Vahid Asnafi, Bertrand Nadel

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

50 Scopus citations

Abstract

T-cell acute lymphoblastic leukaemias (T-ALL) are aggressive malignant proliferations characterized by high relapse rates and great genetic heterogeneity. TAL1 is amongst the most frequently deregulated oncogenes. Yet, over half of the TAL1 + cases lack TAL1 lesions, suggesting unrecognized (epi)genetic deregulation mechanisms. Here we show that TAL1 is normally silenced in the T-cell lineage, and that the polycomb H3K27me3-repressive mark is focally diminished in TAL1 + T-ALLs. Sequencing reveals that >20% of monoallelic TAL1 + patients without previously known alterations display microinsertions or RAG1/2-mediated episomal reintegration in a single site 5″ to TAL1. Using 'allelic-ChIP' and CrispR assays, we demonstrate that such insertions induce a selective switch from H3K27me3 to H3K27ac at the inserted but not the germline allele. We also show that, despite a considerable mechanistic diversity, the mode of oncogenic TAL1 activation, rather than expression levels, impact on clinical outcome. Altogether, these studies establish site-specific epigenetic desilencing as a mechanism of oncogenic activation.

Original language	English
Article number	6094
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms7094
State	Published - Feb 2015
Externally published	Yes

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Navarro, J. M., Touzart, A., Pradel, L. C., Loosveld, M., Koubi, M., Fenouil, R., Le Noir, S., Maqbool, M. A., Morgado, E., Gregoire, C., Jaeger, S., Mamessier, E., Pignon, C., Hacein-Bey-Abina, S., Malissen, B., Gut, M., Gut, I. G., Dombret, H., MacIntyre, E. A., ... Nadel, B. (2015). Site- and allele-specific polycomb dysregulation in T-cell leukaemia. Nature Communications, 6, Article 6094. https://doi.org/10.1038/ncomms7094

@article{c367f8f1886e4f678b5d5b803c63286a,

title = "Site- and allele-specific polycomb dysregulation in T-cell leukaemia",

abstract = "T-cell acute lymphoblastic leukaemias (T-ALL) are aggressive malignant proliferations characterized by high relapse rates and great genetic heterogeneity. TAL1 is amongst the most frequently deregulated oncogenes. Yet, over half of the TAL1 + cases lack TAL1 lesions, suggesting unrecognized (epi)genetic deregulation mechanisms. Here we show that TAL1 is normally silenced in the T-cell lineage, and that the polycomb H3K27me3-repressive mark is focally diminished in TAL1 + T-ALLs. Sequencing reveals that >20\% of monoallelic TAL1 + patients without previously known alterations display microinsertions or RAG1/2-mediated episomal reintegration in a single site 5″ to TAL1. Using 'allelic-ChIP' and CrispR assays, we demonstrate that such insertions induce a selective switch from H3K27me3 to H3K27ac at the inserted but not the germline allele. We also show that, despite a considerable mechanistic diversity, the mode of oncogenic TAL1 activation, rather than expression levels, impact on clinical outcome. Altogether, these studies establish site-specific epigenetic desilencing as a mechanism of oncogenic activation.",

author = "Navarro, \{Jean Marc\} and Aurore Touzart and Pradel, \{Lydie C.\} and Marie Loosveld and Myriam Koubi and Romain Fenouil and \{Le Noir\}, Sandrine and Maqbool, \{Muhammad Ahmad\} and Ester Morgado and Claude Gregoire and Sebastien Jaeger and Emilie Mamessier and Charles Pignon and Salima Hacein-Bey-Abina and Bernard Malissen and Marta Gut and Gut, \{Ivo G.\} and Herv{\'e} Dombret and MacIntyre, \{Elizabeth A.\} and Howe, \{Steven J.\} and Gaspar, \{H. Bobby\} and Thrasher, \{Adrian J.\} and Norbert Ifrah and Dominique Payet-Bornet and Estelle Duprez and Andrau, \{Jean Christophe\} and Vahid Asnafi and Bertrand Nadel",

year = "2015",

month = feb,

doi = "10.1038/ncomms7094",

language = "English",

volume = "6",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

}

Navarro, JM, Touzart, A, Pradel, LC, Loosveld, M, Koubi, M, Fenouil, R, Le Noir, S, Maqbool, MA, Morgado, E, Gregoire, C, Jaeger, S, Mamessier, E, Pignon, C, Hacein-Bey-Abina, S, Malissen, B, Gut, M, Gut, IG, Dombret, H, MacIntyre, EA, Howe, SJ, Gaspar, HB, Thrasher, AJ, Ifrah, N, Payet-Bornet, D, Duprez, E, Andrau, JC, Asnafi, V & Nadel, B 2015, 'Site- and allele-specific polycomb dysregulation in T-cell leukaemia', Nature Communications, vol. 6, 6094. https://doi.org/10.1038/ncomms7094

TY - JOUR

T1 - Site- and allele-specific polycomb dysregulation in T-cell leukaemia

AU - Navarro, Jean Marc

AU - Touzart, Aurore

AU - Pradel, Lydie C.

AU - Loosveld, Marie

AU - Koubi, Myriam

AU - Fenouil, Romain

AU - Le Noir, Sandrine

AU - Maqbool, Muhammad Ahmad

AU - Morgado, Ester

AU - Gregoire, Claude

AU - Jaeger, Sebastien

AU - Mamessier, Emilie

AU - Pignon, Charles

AU - Hacein-Bey-Abina, Salima

AU - Malissen, Bernard

AU - Gut, Marta

AU - Gut, Ivo G.

AU - Dombret, Hervé

AU - MacIntyre, Elizabeth A.

AU - Howe, Steven J.

AU - Gaspar, H. Bobby

AU - Thrasher, Adrian J.

AU - Ifrah, Norbert

AU - Payet-Bornet, Dominique

AU - Duprez, Estelle

AU - Andrau, Jean Christophe

AU - Asnafi, Vahid

AU - Nadel, Bertrand

PY - 2015/2

Y1 - 2015/2

N2 - T-cell acute lymphoblastic leukaemias (T-ALL) are aggressive malignant proliferations characterized by high relapse rates and great genetic heterogeneity. TAL1 is amongst the most frequently deregulated oncogenes. Yet, over half of the TAL1 + cases lack TAL1 lesions, suggesting unrecognized (epi)genetic deregulation mechanisms. Here we show that TAL1 is normally silenced in the T-cell lineage, and that the polycomb H3K27me3-repressive mark is focally diminished in TAL1 + T-ALLs. Sequencing reveals that >20% of monoallelic TAL1 + patients without previously known alterations display microinsertions or RAG1/2-mediated episomal reintegration in a single site 5″ to TAL1. Using 'allelic-ChIP' and CrispR assays, we demonstrate that such insertions induce a selective switch from H3K27me3 to H3K27ac at the inserted but not the germline allele. We also show that, despite a considerable mechanistic diversity, the mode of oncogenic TAL1 activation, rather than expression levels, impact on clinical outcome. Altogether, these studies establish site-specific epigenetic desilencing as a mechanism of oncogenic activation.

AB - T-cell acute lymphoblastic leukaemias (T-ALL) are aggressive malignant proliferations characterized by high relapse rates and great genetic heterogeneity. TAL1 is amongst the most frequently deregulated oncogenes. Yet, over half of the TAL1 + cases lack TAL1 lesions, suggesting unrecognized (epi)genetic deregulation mechanisms. Here we show that TAL1 is normally silenced in the T-cell lineage, and that the polycomb H3K27me3-repressive mark is focally diminished in TAL1 + T-ALLs. Sequencing reveals that >20% of monoallelic TAL1 + patients without previously known alterations display microinsertions or RAG1/2-mediated episomal reintegration in a single site 5″ to TAL1. Using 'allelic-ChIP' and CrispR assays, we demonstrate that such insertions induce a selective switch from H3K27me3 to H3K27ac at the inserted but not the germline allele. We also show that, despite a considerable mechanistic diversity, the mode of oncogenic TAL1 activation, rather than expression levels, impact on clinical outcome. Altogether, these studies establish site-specific epigenetic desilencing as a mechanism of oncogenic activation.

UR - https://www.scopus.com/pages/publications/84923096527

U2 - 10.1038/ncomms7094

DO - 10.1038/ncomms7094

M3 - Article

C2 - 25615415

AN - SCOPUS:84923096527

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 6094

ER -

Site- and allele-specific polycomb dysregulation in T-cell leukaemia

Abstract

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