The USP7-TRIM27 axis mediates non-canonical PRC1.1 function and is a druggable target in leukemia

Henny Maat; Tjerk Jan Atsma; Shanna M. Hogeling; Aida Rodriguez Lopez; Jennifer Jaques; Mirjam Olthuis; Marcel P. de Vries; Chantal Gravesteijn; Annet Z. Brouwers-Vos; Nisha van der Meer; Suzan Datema; Jonas Salzbrunn; Gerwin Huls; Roy Baas; Joost H. A. Martens; Vincent van den Boom; Jan Jacob Schuringa

doi:10.1016/j.isci.2021.102435

The USP7-TRIM27 axis mediates non-canonical PRC1.1 function and is a druggable target in leukemia

Henny Maat, Tjerk Jan Atsma, Shanna M. Hogeling, Aida Rodriguez Lopez, Jennifer Jaques, Mirjam Olthuis, Marcel P. de Vries, Chantal Gravesteijn, Annet Z. Brouwers-Vos, Nisha van der Meer, Suzan Datema, Jonas Salzbrunn, Gerwin Huls, Roy Baas, Joost H. A. Martens, Vincent van den Boom, Jan Jacob Schuringa^*

^*Corresponding author for this work

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

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Abstract

In an attempt to unravel functionality of the non-canonical PRC1.1 Polycomb complex in human leukemogenesis, we show that USP7 and TRIM27 are integral components of PRC1.1. USP7 interactome analyses show that PRC1.1 is the predominant Polycomb complex co-precipitating with USP7. USP7 inhibition results in PRC1.1 disassembly and loss of chromatin binding, coinciding with reduced H2AK119ub and H3K27ac levels and diminished gene transcription of active PRC1.1-controlled loci, whereas H2AK119ub marks are also lost at PRC1 loci. TRIM27 and USP7 are reciprocally required for incorporation into PRC1.1, and TRIM27 knockdown partially rescues USP7 inhibitor sensitivity. USP7 inhibitors effectively impair proliferation in AML cells in vitro, also independent of the USP7-MDM2-TP53 axis, and MLL-AF9-induced leukemia is delayed in vivo in human leukemia xenografts. We propose a model where USP7 counteracts TRIM27 E3 ligase activity, thereby maintaining PRC1.1 integrity and function. Moreover, USP7 inhibition may be a promising new strategy to treat AML patients.

Original language	English
Article number	102435
Number of pages	29
Journal	iScience
Volume	24
Issue number	5
DOIs	https://doi.org/10.1016/j.isci.2021.102435
Publication status	Published - 21-May-2021

Keywords

ACUTE MYELOID-LEUKEMIA
CELL SELF-RENEWAL
POLYCOMB GROUP
H2A UBIQUITYLATION
COMPLEX KARYOTYPE
USP7 INHIBITION
FAMILY-MEMBERS
CPG ISLANDS
STEM-CELLS
CBX FAMILY

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The USP7-TRIM27 axis mediates non-canonical PRC1.1 function and is a druggable target in leukemiaFinal publisher's version, 5.91 MBLicence: CC BY

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Maat, H., Atsma, T. J., Hogeling, S. M., Lopez, A. R., Jaques, J., Olthuis, M., de Vries, M. P., Gravesteijn, C., Brouwers-Vos, A. Z., van der Meer, N., Datema, S., Salzbrunn, J., Huls, G., Baas, R., Martens, J. H. A., van den Boom, V., & Schuringa, J. J. (2021). The USP7-TRIM27 axis mediates non-canonical PRC1.1 function and is a druggable target in leukemia. iScience , 24(5), Article 102435. https://doi.org/10.1016/j.isci.2021.102435

@article{e65f767206be4b15b1831c40936f5487,

title = "The USP7-TRIM27 axis mediates non-canonical PRC1.1 function and is a druggable target in leukemia",

abstract = "In an attempt to unravel functionality of the non-canonical PRC1.1 Polycomb complex in human leukemogenesis, we show that USP7 and TRIM27 are integral components of PRC1.1. USP7 interactome analyses show that PRC1.1 is the predominant Polycomb complex co-precipitating with USP7. USP7 inhibition results in PRC1.1 disassembly and loss of chromatin binding, coinciding with reduced H2AK119ub and H3K27ac levels and diminished gene transcription of active PRC1.1-controlled loci, whereas H2AK119ub marks are also lost at PRC1 loci. TRIM27 and USP7 are reciprocally required for incorporation into PRC1.1, and TRIM27 knockdown partially rescues USP7 inhibitor sensitivity. USP7 inhibitors effectively impair proliferation in AML cells in vitro, also independent of the USP7-MDM2-TP53 axis, and MLL-AF9-induced leukemia is delayed in vivo in human leukemia xenografts. We propose a model where USP7 counteracts TRIM27 E3 ligase activity, thereby maintaining PRC1.1 integrity and function. Moreover, USP7 inhibition may be a promising new strategy to treat AML patients.",

keywords = "ACUTE MYELOID-LEUKEMIA, CELL SELF-RENEWAL, POLYCOMB GROUP, H2A UBIQUITYLATION, COMPLEX KARYOTYPE, USP7 INHIBITION, FAMILY-MEMBERS, CPG ISLANDS, STEM-CELLS, CBX FAMILY",

author = "Henny Maat and Atsma, {Tjerk Jan} and Hogeling, {Shanna M.} and Lopez, {Aida Rodriguez} and Jennifer Jaques and Mirjam Olthuis and {de Vries}, {Marcel P.} and Chantal Gravesteijn and Brouwers-Vos, {Annet Z.} and {van der Meer}, Nisha and Suzan Datema and Jonas Salzbrunn and Gerwin Huls and Roy Baas and Martens, {Joost H. A.} and {van den Boom}, Vincent and Schuringa, {Jan Jacob}",

note = "{\textcopyright} 2021 The Author(s).",

year = "2021",

month = may,

day = "21",

doi = "10.1016/j.isci.2021.102435",

language = "English",

volume = "24",

journal = "iScience ",

issn = "2589-0042",

publisher = "Elsevier",

number = "5",

}

Maat, H, Atsma, TJ, Hogeling, SM, Lopez, AR, Jaques, J, Olthuis, M, de Vries, MP, Gravesteijn, C, Brouwers-Vos, AZ, van der Meer, N, Datema, S, Salzbrunn, J , Huls, G, Baas, R, Martens, JHA, van den Boom, V & Schuringa, JJ 2021, 'The USP7-TRIM27 axis mediates non-canonical PRC1.1 function and is a druggable target in leukemia', iScience , vol. 24, no. 5, 102435. https://doi.org/10.1016/j.isci.2021.102435

TY - JOUR

T1 - The USP7-TRIM27 axis mediates non-canonical PRC1.1 function and is a druggable target in leukemia

AU - Maat, Henny

AU - Atsma, Tjerk Jan

AU - Hogeling, Shanna M.

AU - Lopez, Aida Rodriguez

AU - Jaques, Jennifer

AU - Olthuis, Mirjam

AU - de Vries, Marcel P.

AU - Gravesteijn, Chantal

AU - Brouwers-Vos, Annet Z.

AU - van der Meer, Nisha

AU - Datema, Suzan

AU - Salzbrunn, Jonas

AU - Huls, Gerwin

AU - Baas, Roy

AU - Martens, Joost H. A.

AU - van den Boom, Vincent

AU - Schuringa, Jan Jacob

PY - 2021/5/21

Y1 - 2021/5/21

N2 - In an attempt to unravel functionality of the non-canonical PRC1.1 Polycomb complex in human leukemogenesis, we show that USP7 and TRIM27 are integral components of PRC1.1. USP7 interactome analyses show that PRC1.1 is the predominant Polycomb complex co-precipitating with USP7. USP7 inhibition results in PRC1.1 disassembly and loss of chromatin binding, coinciding with reduced H2AK119ub and H3K27ac levels and diminished gene transcription of active PRC1.1-controlled loci, whereas H2AK119ub marks are also lost at PRC1 loci. TRIM27 and USP7 are reciprocally required for incorporation into PRC1.1, and TRIM27 knockdown partially rescues USP7 inhibitor sensitivity. USP7 inhibitors effectively impair proliferation in AML cells in vitro, also independent of the USP7-MDM2-TP53 axis, and MLL-AF9-induced leukemia is delayed in vivo in human leukemia xenografts. We propose a model where USP7 counteracts TRIM27 E3 ligase activity, thereby maintaining PRC1.1 integrity and function. Moreover, USP7 inhibition may be a promising new strategy to treat AML patients.

AB - In an attempt to unravel functionality of the non-canonical PRC1.1 Polycomb complex in human leukemogenesis, we show that USP7 and TRIM27 are integral components of PRC1.1. USP7 interactome analyses show that PRC1.1 is the predominant Polycomb complex co-precipitating with USP7. USP7 inhibition results in PRC1.1 disassembly and loss of chromatin binding, coinciding with reduced H2AK119ub and H3K27ac levels and diminished gene transcription of active PRC1.1-controlled loci, whereas H2AK119ub marks are also lost at PRC1 loci. TRIM27 and USP7 are reciprocally required for incorporation into PRC1.1, and TRIM27 knockdown partially rescues USP7 inhibitor sensitivity. USP7 inhibitors effectively impair proliferation in AML cells in vitro, also independent of the USP7-MDM2-TP53 axis, and MLL-AF9-induced leukemia is delayed in vivo in human leukemia xenografts. We propose a model where USP7 counteracts TRIM27 E3 ligase activity, thereby maintaining PRC1.1 integrity and function. Moreover, USP7 inhibition may be a promising new strategy to treat AML patients.

KW - ACUTE MYELOID-LEUKEMIA

KW - CELL SELF-RENEWAL

KW - POLYCOMB GROUP

KW - H2A UBIQUITYLATION

KW - COMPLEX KARYOTYPE

KW - USP7 INHIBITION

KW - FAMILY-MEMBERS

KW - CPG ISLANDS

KW - STEM-CELLS

KW - CBX FAMILY

U2 - 10.1016/j.isci.2021.102435

DO - 10.1016/j.isci.2021.102435

M3 - Article

C2 - 34113809

SN - 2589-0042

VL - 24

JO - iScience

JF - iScience

IS - 5

M1 - 102435

ER -

The USP7-TRIM27 axis mediates non-canonical PRC1.1 function and is a druggable target in leukemia

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Keywords

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