• ZFP91 is a bona fide transcription factor that coregulates cell survival with IKZF1 in IMiD-resistant TCLs.

  • CC-92480, by targeting IKZF1 and ZFP91, overcomes IMiD-resistance in TCLs and shows a good therapeutic window for clinical use.

Immunomodulatory (IMiD) agents like lenalidomide and pomalidomide induce the recruitment of IKZF1 and other targets to the CRL4CRBN E3 ubiquitin ligase, resulting in their ubiquitination and degradation. These agents are highly active in B-cell lymphomas and a subset of myeloid diseases but have compromised effects in T-cell lymphomas (TCLs). Here, we show that 2 factors determine resistance to IMiDs among TCLs. First, limited CRBN expression reduces IMiD activity in TCLs but can be overcome by newer-generation degrader CC-92480. Using mass spectrometry, we show that CC-92480 selectively degrades IKZF1 and ZFP91 in TCL cells with greater potency than pomalidomide. As a result, CC-92480 is highly active against multiple TCL subtypes and showed greater efficacy than pomalidomide across 4 in vivo TCL models. Second, we demonstrate that ZFP91 functions as a bona fide transcription factor that coregulates cell survival with IKZF1 in IMiD-resistant TCLs. By activating keynote genes from WNT, NF-kB, and MAP kinase signaling, ZFP91 directly promotes resistance to IKZF1 loss. Moreover, lenalidomide-sensitive TCLs can acquire stable resistance via ZFP91 rewiring, which involves casein kinase 2–mediated c-Jun inactivation. Overall, these findings identify a critical transcription factor network within TCLs and provide clinical proof of concept for the novel therapy using next-generation degraders.

1.
Vose
J
,
Armitage
J
,
Weisenburger
D
;
International T-Cell Lymphoma Project
.
International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes
.
J Clin Oncol.
2008
;
26
(
25
):
4124
-
4130
.
2.
Swerdlow
SH
,
Campo
E
,
Pileri
SA
, et al
.
The 2016 revision of the World Health Organization classification of lymphoid neoplasms
.
Blood.
2016
;
127
(
20
):
2375
-
2390
.
3.
Armitage
JO
.
The aggressive peripheral T-cell lymphomas: 2017
.
Am J Hematol.
2017
;
92
(
7
):
706
-
715
.
4.
Horwitz
S
,
O’Connor
OA
,
Pro
B
, et al;
ECHELON-2 Study Group
.
Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial
.
Lancet.
2019
;
393
(
10168
):
229
-
240
.
5.
Ellin
F
,
Landström
J
,
Jerkeman
M
,
Relander
T
.
Real-world data on prognostic factors and treatment in peripheral T-cell lymphomas: a study from the Swedish Lymphoma Registry
.
Blood.
2014
;
124
(
10
):
1570
-
1577
.
6.
Jacobsen
ED
,
Weinstock
DM
.
Challenges and implications of genomics for T-cell lymphomas
.
Hematology (Am Soc Hematol Educ Program).
2018
;
2018
(
1
):
63
-
68
.
7.
Krönke
J
,
Udeshi
ND
,
Narla
A
, et al
.
Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells
.
Science.
2014
;
343
(
6168
):
301
-
305
.
8.
Lu
G
,
Middleton
RE
,
Sun
H
, et al
.
The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins
.
Science.
2014
;
343
(
6168
):
305
-
309
.
9.
Krönke
J
,
Fink
EC
,
Hollenbach
PW
, et al
.
Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS
.
Nature.
2015
;
523
(
7559
):
183
-
188
.
10.
Minzel
W
,
Venkatachalam
A
,
Fink
A
, et al
.
Small molecules co-targeting CKIα and the transcriptional kinases CDK7/9 control AML in preclinical models
.
Cell.
2018
;
175
(
1
):
171
-
185.e25
.
11.
Chamberlain
PP
,
Lopez-Girona
A
,
Miller
K
, et al
.
Structure of the human Cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs
.
Nat Struct Mol Biol.
2014
;
21
(
9
):
803
-
809
.
12.
Powell
MD
,
Read
KA
,
Sreekumar
BK
,
Oestreich
KJ
.
Ikaros zinc finger transcription factors: regulators of cytokine signaling pathways and CD4+ T helper cell differentiation
.
Front Immunol.
2019
;
10
:
1299
.
13.
Morschhauser
F
,
Fitoussi
O
,
Haioun
C
, et al
.
A phase 2, multicentre, single-arm, open-label study to evaluate the safety and efficacy of single-agent lenalidomide (Revlimid) in subjects with relapsed or refractory peripheral T-cell non-Hodgkin lymphoma: the EXPECT trial
.
Eur J Cancer.
2013
;
49
(
13
):
2869
-
2876
.
14.
Lemonnier
F
,
Safar
V
,
Beldi-Ferchiou
A
, et al
.
Integrative analysis of a phase 2 trial combining lenalidomide with CHOP in angioimmunoblastic T-cell lymphoma
.
Blood Adv.
2021
;
5
(
2
):
539
-
548
.
15.
Ng
SY
,
Yoshida
N
,
Christie
AL
, et al
.
Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models
.
Nat Commun.
2018
;
9
(
1
):
2024
.
16.
An
J
,
Ponthier
CM
,
Sack
R
, et al
.
pSILAC mass spectrometry reveals ZFP91 as IMiD-dependent substrate of the CRL4CRBN ubiquitin ligase
.
Nat Commun.
2017
;
8
(
1
):
15398
.
17.
Paschke
L
,
Jopek
K
,
Szyszka
M
,
Tyczewska
M
,
Malendowicz
LK
,
Rucinski
M
.
ZFP91 zinc finger protein expression pattern in normal tissues and cancers
.
Oncol Lett.
2019
;
17
(
3
):
3599
-
3606
.
18.
Unoki
M
,
Okutsu
J
,
Nakamura
Y
.
Identification of a novel human gene, ZFP91, involved in acute myelogenous leukemia
.
Int J Oncol.
2003
;
22
(
6
):
1217
-
1223
.
19.
Mi
C
,
Wang
Z
,
Li
MY
,
Zhang
ZH
,
Ma
J
,
Jin
X
.
Zinc finger protein 91 positively regulates the production of IL-1β in macrophages by activation of MAPKs and non-canonical caspase-8 inflammasome
.
Br J Pharmacol.
2018
;
175
(
23
):
4338
-
4352
.
20.
Patil
A
,
Manzano
M
,
Gottwein
E
.
CK1α and IRF4 are essential and independent effectors of immunomodulatory drugs in primary effusion lymphoma
.
Blood.
2018
;
132
(
6
):
577
-
586
.
21.
Hopfinger
G
,
Nösslinger
T
,
Lang
A
, et al
.
Lenalidomide in combination with vorinostat and dexamethasone for the treatment of relapsed/refractory peripheral T cell lymphoma (PTCL): report of a phase I/II trial
.
Ann Hematol.
2014
;
93
(
3
):
459
-
462
.
22.
Umetsu
SE
,
Winandy
S
.
Ikaros is a regulator of Il10 expression in CD4+ T cells
.
J Immunol.
2009
;
183
(
9
):
5518
-
5525
.
23.
Fedele
PL
,
Willis
SN
,
Liao
Y
, et al
.
IMiDs prime myeloma cells for daratumumab-mediated cytotoxicity through loss of Ikaros and Aiolos
.
Blood.
2018
;
132
(
20
):
2166
-
2178
.
24.
Sievers
QL
,
Gasser
JA
,
Cowley
GS
,
Fischer
ES
,
Ebert
BL
.
Genome-wide screen identifies cullin-RING ligase machinery required for lenalidomide-dependent CRL4CRBN activity
.
Blood.
2018
;
132
(
12
):
1293
-
1303
.
25.
Mo
Z
,
Wood
S
,
Namiranian
S
, et al
.
Deciphering the mechanisms of CC-122 resistance in DLBCL via a genome-wide CRISPR screen
.
Blood Adv.
2021
;
5
(
7
):
2027
-
2039
.
26.
Hansen
JD
,
Correa
M
,
Nagy
MA
, et al
.
Discovery of CRBN E3 Ligase Modulator CC-92480 for the Treatment of Relapsed and Refractory Multiple Myeloma
.
J Med Chem.
2020
;
63
(
13
):
6648
-
6676
.
27.
Bjorklund
CC
,
Kang
J
,
Amatangelo
M
, et al
.
Iberdomide (CC-220) is a potent cereblon E3 ligase modulator with antitumor and immunostimulatory activities in lenalidomide- and pomalidomide-resistant multiple myeloma cells with dysregulated CRBN
.
Leukemia.
2020
;
34
(
4
):
1197
-
1201
.
28.
Yamamoto
J
,
Suwa
T
,
Murase
Y
, et al
.
ARID2 is a pomalidomide-dependent CRL4CRBN substrate in multiple myeloma cells
.
Nat Chem Biol.
2020
;
16
(
11
):
1208
-
1217
.
29.
Matsuoka
A
,
Tochigi
A
,
Kishimoto
M
, et al
.
Lenalidomide induces cell death in an MDS-derived cell line with deletion of chromosome 5q by inhibition of cytokinesis
.
Leukemia.
2010
;
24
(
4
):
748
-
755
.
30.
Angel
P
,
Hattori
K
,
Smeal
T
,
Karin
M
.
The jun proto-oncogene is positively autoregulated by its product, Jun/AP-1
.
Cell.
1988
;
55
(
5
):
875
-
885
.
31.
Lin
A
,
Frost
J
,
Deng
T
, et al
.
Casein kinase II is a negative regulator of c-Jun DNA binding and AP-1 activity
.
Cell.
1992
;
70
(
5
):
777
-
789
.
32.
Heavican
TB
,
Bouska
A
,
Yu
J
, et al
.
Genetic drivers of oncogenic pathways in molecular subgroups of peripheral T-cell lymphoma
.
Blood.
2019
;
133
(
15
):
1664
-
1676
.
33.
Dobay
MP
,
Lemonnier
F
,
Missiaglia
E
, et al
.
Integrative clinicopathological and molecular analyses of angioimmunoblastic T-cell lymphoma and other nodal lymphomas of follicular helper T-cell origin
.
Haematologica.
2017
;
102
(
4
):
e148
-
e151
.
34.
Saotome
Y
,
Winter
CG
,
Hirsh
D
.
A widely expressed novel C2H2 zinc-finger protein with multiple consensus phosphorylation sites is conserved in mouse and man
.
Gene.
1995
;
152
(
2
):
233
-
238
.
35.
Ma
J
,
Mi
C
,
Wang
KS
,
Lee
JJ
,
Jin
X
.
Zinc finger protein 91 (ZFP91) activates HIF-1α via NF-κB/p65 to promote proliferation and tumorigenesis of colon cancer
.
Oncotarget.
2016
;
7
(
24
):
36551
-
36562
.
36.
Wang
L
,
Liu
Q
,
Kitamoto
T
,
Hou
J
,
Qin
J
,
Accili
D
.
Identification of insulin-responsive transcription factors that regulate glucose production by hepatocytes
.
Diabetes.
2019
;
68
(
6
):
1156
-
1167
.
37.
Jin
X
,
Jin
HR
,
Jung
HS
,
Lee
SJ
,
Lee
JH
,
Lee
JJ
.
An atypical E3 ligase zinc finger protein 91 stabilizes and activates NF-kappaB-inducing kinase via Lys63-linked ubiquitination
.
J Biol Chem.
2010
;
285
(
40
):
30539
-
30547
.
38.
Wang
A
,
Ding
L
,
Wu
Z
, et al
.
ZFP91 is required for the maintenance of regulatory T cell homeostasis and function
.
J Exp Med.
2021
;
218
(
2
):
e20201217
.
39.
Wang
F
,
Zhang
Y
,
Yu
X
, et al
.
ZFP91 disturbs metabolic fitness and antitumor activity of tumor-infiltrating T cells
.
J Clin Invest.
2021
;
131
(
19
):
e144318
.
40.
Raha
D
,
Wang
Z
,
Moqtaderi
Z
, et al
.
Close association of RNA polymerase II and many transcription factors with Pol III genes
.
Proc Natl Acad Sci USA.
2010
;
107
(
8
):
3639
-
3644
.
41.
Pope
BD
,
Ryba
T
,
Dileep
V
, et al
.
Topologically associating domains are stable units of replication-timing regulation
.
Nature.
2014
;
515
(
7527
):
402
-
405
.
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