ASXL2 is essential for haematopoiesis and acts as a haploinsufficient tumour suppressor in leukemia

Jean Baptiste Micol; Alessandro Pastore; Daichi Inoue; Nicolas Duployez; Eunhee Kim; Stanley Chun Wei Lee; Benjamin H. Durham; Young Rock Chung; Hana Cho; Xiao Jing Zhang; Akihide Yoshimi; Andrei Krivtsov; Richard Koche; Eric Solary; Amit Sinha; Claude Preudhomme; Omar Abdel-Wahab

doi:10.1038/ncomms15429

ASXL2 is essential for haematopoiesis and acts as a haploinsufficient tumour suppressor in leukemia

Jean Baptiste Micol, Alessandro Pastore, Daichi Inoue, Nicolas Duployez, Eunhee Kim, Stanley Chun Wei Lee, Benjamin H. Durham, Young Rock Chung, Hana Cho, Xiao Jing Zhang, Akihide Yoshimi, Andrei Krivtsov, Richard Koche, Eric Solary, Amit Sinha, Claude Preudhomme, Omar Abdel-Wahab

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Résumé

Additional sex combs-like (ASXL) proteins are mammalian homologues of additional sex combs (Asx), a regulator of trithorax and polycomb function in Drosophila. While there has been great interest in ASXL1 due to its frequent mutation in leukemia, little is known about its paralog ASXL2, which is frequently mutated in acute myeloid leukemia patients bearing the RUNX1-RUNX1T1 (AML1-ETO) fusion. Here we report that ASXL2 is required for normal haematopoiesis with distinct, non-overlapping effects from ASXL1 and acts as a haploinsufficient tumour suppressor. While Asxl2 was required for normal haematopoietic stem cell self-renewal, Asxl2 loss promoted AML1-ETO leukemogenesis. Moreover, ASXL2 target genes strongly overlapped with those of RUNX1 and AML1-ETO and ASXL2 loss was associated with increased chromatin accessibility at putative enhancers of key leukemogenic loci. These data reveal that Asxl2 is a critical regulator of haematopoiesis and mediates transcriptional effects that promote leukemogenesis driven by AML1-ETO.

langue originale	Anglais
Numéro d'article	15429
journal	Nature Communications
Volume	8
Les DOIs	https://doi.org/10.1038/ncomms15429
état	Publié - 18 mai 2017

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10.1038/ncomms15429

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Micol, J. B., Pastore, A., Inoue, D., Duployez, N., Kim, E., Lee, S. C. W., Durham, B. H., Chung, Y. R., Cho, H., Zhang, X. J., Yoshimi, A., Krivtsov, A., Koche, R., Solary, E., Sinha, A., Preudhomme, C., & Abdel-Wahab, O. (2017). ASXL2 is essential for haematopoiesis and acts as a haploinsufficient tumour suppressor in leukemia. Nature Communications, 8, Article 15429. https://doi.org/10.1038/ncomms15429

@article{bc915a1829ca471998f3d5a6965394c8,

title = "ASXL2 is essential for haematopoiesis and acts as a haploinsufficient tumour suppressor in leukemia",

abstract = "Additional sex combs-like (ASXL) proteins are mammalian homologues of additional sex combs (Asx), a regulator of trithorax and polycomb function in Drosophila. While there has been great interest in ASXL1 due to its frequent mutation in leukemia, little is known about its paralog ASXL2, which is frequently mutated in acute myeloid leukemia patients bearing the RUNX1-RUNX1T1 (AML1-ETO) fusion. Here we report that ASXL2 is required for normal haematopoiesis with distinct, non-overlapping effects from ASXL1 and acts as a haploinsufficient tumour suppressor. While Asxl2 was required for normal haematopoietic stem cell self-renewal, Asxl2 loss promoted AML1-ETO leukemogenesis. Moreover, ASXL2 target genes strongly overlapped with those of RUNX1 and AML1-ETO and ASXL2 loss was associated with increased chromatin accessibility at putative enhancers of key leukemogenic loci. These data reveal that Asxl2 is a critical regulator of haematopoiesis and mediates transcriptional effects that promote leukemogenesis driven by AML1-ETO.",

author = "Micol, {Jean Baptiste} and Alessandro Pastore and Daichi Inoue and Nicolas Duployez and Eunhee Kim and Lee, {Stanley Chun Wei} and Durham, {Benjamin H.} and Chung, {Young Rock} and Hana Cho and Zhang, {Xiao Jing} and Akihide Yoshimi and Andrei Krivtsov and Richard Koche and Eric Solary and Amit Sinha and Claude Preudhomme and Omar Abdel-Wahab",

note = "Publisher Copyright: {\textcopyright} 2017 The Author(s).",

year = "2017",

month = may,

day = "18",

doi = "10.1038/ncomms15429",

language = "English",

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journal = "Nature Communications",

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Micol, JB, Pastore, A, Inoue, D, Duployez, N, Kim, E, Lee, SCW, Durham, BH, Chung, YR, Cho, H, Zhang, XJ, Yoshimi, A, Krivtsov, A, Koche, R, Solary, E, Sinha, A, Preudhomme, C & Abdel-Wahab, O 2017, 'ASXL2 is essential for haematopoiesis and acts as a haploinsufficient tumour suppressor in leukemia', Nature Communications, VOL. 8, 15429. https://doi.org/10.1038/ncomms15429

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T1 - ASXL2 is essential for haematopoiesis and acts as a haploinsufficient tumour suppressor in leukemia

AU - Micol, Jean Baptiste

AU - Pastore, Alessandro

AU - Inoue, Daichi

AU - Duployez, Nicolas

AU - Kim, Eunhee

AU - Lee, Stanley Chun Wei

AU - Durham, Benjamin H.

AU - Chung, Young Rock

AU - Cho, Hana

AU - Zhang, Xiao Jing

AU - Yoshimi, Akihide

AU - Krivtsov, Andrei

AU - Koche, Richard

AU - Solary, Eric

AU - Sinha, Amit

AU - Preudhomme, Claude

AU - Abdel-Wahab, Omar

PY - 2017/5/18

Y1 - 2017/5/18

N2 - Additional sex combs-like (ASXL) proteins are mammalian homologues of additional sex combs (Asx), a regulator of trithorax and polycomb function in Drosophila. While there has been great interest in ASXL1 due to its frequent mutation in leukemia, little is known about its paralog ASXL2, which is frequently mutated in acute myeloid leukemia patients bearing the RUNX1-RUNX1T1 (AML1-ETO) fusion. Here we report that ASXL2 is required for normal haematopoiesis with distinct, non-overlapping effects from ASXL1 and acts as a haploinsufficient tumour suppressor. While Asxl2 was required for normal haematopoietic stem cell self-renewal, Asxl2 loss promoted AML1-ETO leukemogenesis. Moreover, ASXL2 target genes strongly overlapped with those of RUNX1 and AML1-ETO and ASXL2 loss was associated with increased chromatin accessibility at putative enhancers of key leukemogenic loci. These data reveal that Asxl2 is a critical regulator of haematopoiesis and mediates transcriptional effects that promote leukemogenesis driven by AML1-ETO.

AB - Additional sex combs-like (ASXL) proteins are mammalian homologues of additional sex combs (Asx), a regulator of trithorax and polycomb function in Drosophila. While there has been great interest in ASXL1 due to its frequent mutation in leukemia, little is known about its paralog ASXL2, which is frequently mutated in acute myeloid leukemia patients bearing the RUNX1-RUNX1T1 (AML1-ETO) fusion. Here we report that ASXL2 is required for normal haematopoiesis with distinct, non-overlapping effects from ASXL1 and acts as a haploinsufficient tumour suppressor. While Asxl2 was required for normal haematopoietic stem cell self-renewal, Asxl2 loss promoted AML1-ETO leukemogenesis. Moreover, ASXL2 target genes strongly overlapped with those of RUNX1 and AML1-ETO and ASXL2 loss was associated with increased chromatin accessibility at putative enhancers of key leukemogenic loci. These data reveal that Asxl2 is a critical regulator of haematopoiesis and mediates transcriptional effects that promote leukemogenesis driven by AML1-ETO.

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