TY - JOUR
T1 - Methyltransferase inhibitors restore SATB1 protective activity against cutaneous T cell lymphoma in mice
AU - Harro, Carly M.
AU - Perez-Sanz, Jairo
AU - Costich, Tara Lee
AU - Payne, Kyle K.
AU - Anadon, Carmen M.
AU - Chaurio, Ricardo A.
AU - Biswas, Subir
AU - Mandal, Gunjan
AU - Rigolizzo, Kristen E.
AU - Sprenger, Kimberly B.
AU - Mine, Jessica A.
AU - Showe, Louise C.
AU - Yu, Xiaoqing
AU - Liu, Kebin
AU - Rodriguez, Paulo C.
AU - Pinilla-Ibarz, Javier
AU - Sokol, Lubomir
AU - Conejo-Garcia, Jose R.
N1 - Funding Information:
Authorship note: CMH and JPS contributed equally to this work. Conflict of interest: KL holds the US patent 10,577,371 B2, “Small Molecule Histone Methyltransfease SUV39H1 Inhibitor and Uses Thereof.” JPI receives funding from TG therapeutics, MEI, and Sunesis, and consulting fees from Janssen, Abbvie, TG therapeutics, Novartis, and AstraZeneca. LS is an advisor for Kyowa-Kirin, Inc and Kymera Therapeutics, and receives clinical research funding from EUSA Pharma, LLC. JRCG receives funding and consulting fees from Anixa Biosciences and Compass Therapeutics, and consulting fees from Leidos. Copyright: © 2021, American Society for Clinical Investigation. Submitted: December 12, 2019; Accepted: November 25, 2020; Published: February 1, 2021. Reference information: J Clin Invest. 2021;131(3):e135711. https://doi.org/10.1172/JCI135711.
Funding Information:
This study was supported by NIH grants R01CA240434, R01CA157664, and R01CA124515. KKP was supported by NIH T32CA009140 and an American Cancer Society Postdoctoral Fellowship (PF-18-041-1-LIB). LCS was supported by NIH U01 CA200495. This work has been supported in part by the Flow Cytometry Core, Molecular Genomics Core, and Analytic Microscopy Core facilities at the H. Lee Moffitt Cancer Center & Research Institute, an NCI-designated Comprehensive Cancer Center (P30-CA076292).
Publisher Copyright:
Copyright: © 2021, American Society for Clinical Investigation.
PY - 2021/2/1
Y1 - 2021/2/1
N2 - Cutaneous T cell lymphoma (CTCL) has a poorly understood etiology and no known cure. Using conditional knockout mice, we found that ablation of the genomic organizer special AT-rich sequence-binding protein 1 (Satb1) caused malignant transformation of mature, skin-homing, Notch-activated CD4+ and CD8+ T cells into progressively fatal lymphoma. Mechanistically, Satb1 restrained Stat5 phosphorylation and the expression of skin-homing chemokine receptors in mature T cells. Notably, methyltransferase-dependent epigenetic repression of SATB1 was universally found in human Sézary syndrome, but not in other peripheral T cell malignancies. H3K27 and H3K9 trimethylation occluded the SATB1 promoter in Sézary cells, while inhibition of SUV39H1/2 methyltransferases (unlike EZH2 inhibition) restored protective SATB1 expression and selectively abrogated the growth of primary Sézary cells more effectively than romidepsin. Therefore, inhibition of methyltransferases that silence SATB1 could address an unmet need for patients with mycosis fungoides/Sézary syndrome, a set of incurable diseases.
AB - Cutaneous T cell lymphoma (CTCL) has a poorly understood etiology and no known cure. Using conditional knockout mice, we found that ablation of the genomic organizer special AT-rich sequence-binding protein 1 (Satb1) caused malignant transformation of mature, skin-homing, Notch-activated CD4+ and CD8+ T cells into progressively fatal lymphoma. Mechanistically, Satb1 restrained Stat5 phosphorylation and the expression of skin-homing chemokine receptors in mature T cells. Notably, methyltransferase-dependent epigenetic repression of SATB1 was universally found in human Sézary syndrome, but not in other peripheral T cell malignancies. H3K27 and H3K9 trimethylation occluded the SATB1 promoter in Sézary cells, while inhibition of SUV39H1/2 methyltransferases (unlike EZH2 inhibition) restored protective SATB1 expression and selectively abrogated the growth of primary Sézary cells more effectively than romidepsin. Therefore, inhibition of methyltransferases that silence SATB1 could address an unmet need for patients with mycosis fungoides/Sézary syndrome, a set of incurable diseases.
UR - http://www.scopus.com/inward/record.url?scp=85100267298&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85100267298&partnerID=8YFLogxK
U2 - 10.1172/JCI135711
DO - 10.1172/JCI135711
M3 - Article
C2 - 33270606
AN - SCOPUS:85100267298
SN - 0021-9738
VL - 131
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 3
M1 - e135711
ER -
