PHF19 inhibition as a therapeutic target in multiple myeloma

Carolina D. Schinke; Jordan T. Bird; Pingping Qu; Shmuel Yaccoby; Valeriy V. Lyzogubov; Randal Shelton; Wen Ling; Eileen M. Boyle; Sharyu Deshpande; Stephanie D. Byrum; Charity Washam; Samuel Mackintosh; Owen Stephens; Sharmilan Thanendrarajan; Maurizio Zangari; John Shaughnessy; Fenghuang Zhan; Bart Barlogie; Frits van Rhee; Brian A. Walker

doi:10.1016/j.retram.2021.103290

PHF19 inhibition as a therapeutic target in multiple myeloma

Carolina D. Schinke, Jordan T. Bird, Pingping Qu, Shmuel Yaccoby, Valeriy V. Lyzogubov, Randal Shelton, Wen Ling, Eileen M. Boyle, Sharyu Deshpande, Stephanie D. Byrum, Charity Washam, Samuel Mackintosh, Owen Stephens, Sharmilan Thanendrarajan, Maurizio Zangari, John Shaughnessy, Fenghuang Zhan, Bart Barlogie, Frits van Rhee, Brian A. Walker

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Abstract

Epigenetic deregulation is increasingly recognized as a contributing pathological factor in multiple myeloma (MM). In particular tri-methylation of H3 lysine 27 (H3K27me3), which is catalyzed by PHD finger protein 19 (PHF19), a subunit of the Polycomb Repressive Complex 2 (PRC2), has recently shown to be a crucial mediator of MM tumorigenicity. Overexpression of PHF19 in MM has been associated with worse clinical outcome. Yet, while there is mounting evidence that PHF19 overexpression plays a crucial role in MM carcinogenesis downstream mechanisms remain to be elucidated. In the current study we use a functional knock down (KD) of PHF19 to investigate the biological role of PHF19 and show that PHF19KD leads to decreased tumor growth in vitro and in vivo. Expression of major cancer players such as bcl2, myc and EGR1 were decreased upon PHF19KD further underscoring the role of PHF19 in MM biology. Additionally, our results highlighted the prognostic impact of PHF19 overexpression, which was significantly associated with worse survival. Overall, our study underscores the premise that targeting the PHF19-PRC2 complex would open up avenues for novel MM therapies.

Original language	English
Article number	103290
Journal	Current Research in Translational Medicine
Volume	69
Issue number	3
DOIs	https://doi.org/10.1016/j.retram.2021.103290
State	Published - Jul 2021

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Schinke, C. D., Bird, J. T., Qu, P., Yaccoby, S., Lyzogubov, V. V., Shelton, R., Ling, W., Boyle, E. M., Deshpande, S., Byrum, S. D., Washam, C., Mackintosh, S., Stephens, O., Thanendrarajan, S., Zangari, M., Shaughnessy, J., Zhan, F., Barlogie, B., van Rhee, F., & Walker, B. A. (2021). PHF19 inhibition as a therapeutic target in multiple myeloma. Current Research in Translational Medicine, 69(3), Article 103290. https://doi.org/10.1016/j.retram.2021.103290

@article{15e5dc4660b946999c257bd33f187e59,

title = "PHF19 inhibition as a therapeutic target in multiple myeloma",

abstract = "Epigenetic deregulation is increasingly recognized as a contributing pathological factor in multiple myeloma (MM). In particular tri-methylation of H3 lysine 27 (H3K27me3), which is catalyzed by PHD finger protein 19 (PHF19), a subunit of the Polycomb Repressive Complex 2 (PRC2), has recently shown to be a crucial mediator of MM tumorigenicity. Overexpression of PHF19 in MM has been associated with worse clinical outcome. Yet, while there is mounting evidence that PHF19 overexpression plays a crucial role in MM carcinogenesis downstream mechanisms remain to be elucidated. In the current study we use a functional knock down (KD) of PHF19 to investigate the biological role of PHF19 and show that PHF19KD leads to decreased tumor growth in vitro and in vivo. Expression of major cancer players such as bcl2, myc and EGR1 were decreased upon PHF19KD further underscoring the role of PHF19 in MM biology. Additionally, our results highlighted the prognostic impact of PHF19 overexpression, which was significantly associated with worse survival. Overall, our study underscores the premise that targeting the PHF19-PRC2 complex would open up avenues for novel MM therapies.",

author = "Schinke, {Carolina D.} and Bird, {Jordan T.} and Pingping Qu and Shmuel Yaccoby and Lyzogubov, {Valeriy V.} and Randal Shelton and Wen Ling and Boyle, {Eileen M.} and Sharyu Deshpande and Byrum, {Stephanie D.} and Charity Washam and Samuel Mackintosh and Owen Stephens and Sharmilan Thanendrarajan and Maurizio Zangari and John Shaughnessy and Fenghuang Zhan and Bart Barlogie and {van Rhee}, Frits and Walker, {Brian A.}",

note = "Publisher Copyright: {\textcopyright} 2021 Elsevier Masson SAS",

year = "2021",

month = jul,

doi = "10.1016/j.retram.2021.103290",

language = "English",

volume = "69",

journal = "Current Research in Translational Medicine",

issn = "2452-3186",

publisher = "Elsevier Masson s.r.l.",

number = "3",

}

Schinke, CD, Bird, JT, Qu, P, Yaccoby, S, Lyzogubov, VV, Shelton, R, Ling, W, Boyle, EM, Deshpande, S, Byrum, SD, Washam, C, Mackintosh, S, Stephens, O, Thanendrarajan, S, Zangari, M, Shaughnessy, J, Zhan, F, Barlogie, B, van Rhee, F & Walker, BA 2021, 'PHF19 inhibition as a therapeutic target in multiple myeloma', Current Research in Translational Medicine, vol. 69, no. 3, 103290. https://doi.org/10.1016/j.retram.2021.103290

TY - JOUR

T1 - PHF19 inhibition as a therapeutic target in multiple myeloma

AU - Schinke, Carolina D.

AU - Bird, Jordan T.

AU - Qu, Pingping

AU - Yaccoby, Shmuel

AU - Lyzogubov, Valeriy V.

AU - Shelton, Randal

AU - Ling, Wen

AU - Boyle, Eileen M.

AU - Deshpande, Sharyu

AU - Byrum, Stephanie D.

AU - Washam, Charity

AU - Mackintosh, Samuel

AU - Stephens, Owen

AU - Thanendrarajan, Sharmilan

AU - Zangari, Maurizio

AU - Shaughnessy, John

AU - Zhan, Fenghuang

AU - Barlogie, Bart

AU - van Rhee, Frits

AU - Walker, Brian A.

PY - 2021/7

Y1 - 2021/7

N2 - Epigenetic deregulation is increasingly recognized as a contributing pathological factor in multiple myeloma (MM). In particular tri-methylation of H3 lysine 27 (H3K27me3), which is catalyzed by PHD finger protein 19 (PHF19), a subunit of the Polycomb Repressive Complex 2 (PRC2), has recently shown to be a crucial mediator of MM tumorigenicity. Overexpression of PHF19 in MM has been associated with worse clinical outcome. Yet, while there is mounting evidence that PHF19 overexpression plays a crucial role in MM carcinogenesis downstream mechanisms remain to be elucidated. In the current study we use a functional knock down (KD) of PHF19 to investigate the biological role of PHF19 and show that PHF19KD leads to decreased tumor growth in vitro and in vivo. Expression of major cancer players such as bcl2, myc and EGR1 were decreased upon PHF19KD further underscoring the role of PHF19 in MM biology. Additionally, our results highlighted the prognostic impact of PHF19 overexpression, which was significantly associated with worse survival. Overall, our study underscores the premise that targeting the PHF19-PRC2 complex would open up avenues for novel MM therapies.

AB - Epigenetic deregulation is increasingly recognized as a contributing pathological factor in multiple myeloma (MM). In particular tri-methylation of H3 lysine 27 (H3K27me3), which is catalyzed by PHD finger protein 19 (PHF19), a subunit of the Polycomb Repressive Complex 2 (PRC2), has recently shown to be a crucial mediator of MM tumorigenicity. Overexpression of PHF19 in MM has been associated with worse clinical outcome. Yet, while there is mounting evidence that PHF19 overexpression plays a crucial role in MM carcinogenesis downstream mechanisms remain to be elucidated. In the current study we use a functional knock down (KD) of PHF19 to investigate the biological role of PHF19 and show that PHF19KD leads to decreased tumor growth in vitro and in vivo. Expression of major cancer players such as bcl2, myc and EGR1 were decreased upon PHF19KD further underscoring the role of PHF19 in MM biology. Additionally, our results highlighted the prognostic impact of PHF19 overexpression, which was significantly associated with worse survival. Overall, our study underscores the premise that targeting the PHF19-PRC2 complex would open up avenues for novel MM therapies.

UR - http://www.scopus.com/inward/record.url?scp=85104574576&partnerID=8YFLogxK

U2 - 10.1016/j.retram.2021.103290

DO - 10.1016/j.retram.2021.103290

M3 - Article

C2 - 33894670

AN - SCOPUS:85104574576

SN - 2452-3186

VL - 69

JO - Current Research in Translational Medicine

JF - Current Research in Translational Medicine

IS - 3

M1 - 103290

ER -

PHF19 inhibition as a therapeutic target in multiple myeloma

Abstract

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