Brief Report

LYMPHOID NEOPLASIA

SGK1 mutations in DLBCL generate hyperstable protein

neoisoforms that promote AKT independence
Jie Gao,1,2 Eirini Sidiropoulou,1,2 Ieuan Walker,1,2 Joanna A. Krupka,1,3 Karol Mizielinski,1,2 Zelvera Usheva,1,2 Shamith A. Samarajiwa,3
and Daniel J. Hodson1,2
1
Wellcome-MRC Cambridge Stem Cell Institute, Cambridge, United Kingdom; 2Department of Haematology, University of Cambridge, Cambridge, United
Kingdom; and 3MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, United Kingdom

KEY POINTS Serum and glucocorticoid-regulated kinase 1 (SGK1) is one of the most frequently mutated

 Distinct classes of SGK1 genes in diffuse large B-cell lymphoma (DLBCL). However, little is known about its function
mutations identified in or the consequence of its mutation. The frequent finding of truncating mutations has led
DLBCL converge on the to the widespread assumption that these represent loss-of-function variants and, accord-
production of stabilized ingly, that SGK1 must act as a tumor suppressor. In this study, instead, the most common
SGK1 protein and AKT
independence. SGK1 mutations led to production of aberrantly spliced messenger RNA neoisoforms in
which translation is initiated from downstream methionines. The resulting N-terminal trun-
 SGK1 should be cated protein isoforms showed increased expression related to the exclusion of an
considered as an
N-terminal degradation domain. However, they retained a functional kinase domain, the
oncogene and a
potential therapeutic overexpression of which rendered cells resistant to AKT inhibition, in part because of
target in DLBCL. increased phosphorylation of GSK3B. These findings challenge the prevailing assumption
that SGK1 is a tumor-suppressor gene in DLBCL and provide the impetus to explore fur-
ther the pharmacological inhibition of SGK1 as a therapeutic strategy for DLBCL.

Introduction epithelial malignancy, the question arises as to why loss-of-func-

Serum and glucocorticoid-regulated kinase 1 (SGK1) has
emerged as one of the most frequently mutated genes in
DLBCL1,2 and also in lymphocyte-predominant Hodgkin lym-
phoma.3 Moreover, the presence of SGK1 mutation was the
dominant genetic feature driving classification into the molecular
subtypes termed “ST2” (for SGK1/TET2), “SGK1,” or “C4” in
the 3 recent DLBCL genomic clustering studies.4-7 Despite the
prominence of SGK1 mutations, little is known about its function
or the molecular consequences of its mutation in B-cell lym-
phoma . However, the pattern of mutations, enriched for non-
sense and splice variants, has led to the assumption that these
represent loss-of-function mutations and that SGK1 must exert a
tumor-suppressor function in DLBCL.4,8-10
SGK1 belongs to a family of serine and threonine kinases that
includes AKT and is positively regulated by mTORC2 and
PDK1.11 It acts as an AKT-independent effector of PI3K during
cancer development12 and mediates resistance to AKT inhibition
in epithelial cancers.13,14 Downstream targets of SGK1 are
poorly defined, but there appears to be overlap with AKT.11
SGK1 is overexpressed in many solid-organ malignancies,
including breast, prostate, and colon, where it is considered to
function as an oncogene and is an attractive target for therapeu-
tic inhibition.11,15 Given its apparent oncogenic function in
tion mutation of SGK1 should be advantageous in B-cell
lymphoma.
Study design
CRISPR-edited SGK1 mutant and control cell line clones were
generated by electroporation of the PX458 plasmid (Addgene)
encoding Cas9 and single guide RNA (gRNA) and a single-
stranded 90-nucleotide DNA template containing the desired
mutation and a SalI restriction site to facilitate screening. Cor-
rectly targeted clones were verified by Sanger sequencing. The
resulting messenger RNA (mRNA) isoforms were identified using
the 5' RACE System (rapid amplification of cDNA ends), version
2.0 (18374058; Invitrogen/Thermo Fisher Scientific), per the
manufacturer’s instructions. Full experimental details are pro-
vided in the supplemental Methods, available on the Blood
Web site.
Results and discussion
We pooled mutation data from 5 DLBCL sequencing stud-
ies.1,2,5,6,8 The results revealed widely scattered SGK1 mutations
that included missense, nonsense, and splice variants, which pre-
dominantly affected the 5' region of the gene (Figure 1A; supple-
mental Table 1). This finding is consistent with SGK1 as a known

© 2021 by The American Society of Hematology blood® 16 SEPTEMBER 2021 | VOLUME 138, NUMBER 11 959
 A B 50
50 Chr6:134,495,724 Chr6:134,495,724

40

Mutation frequency
Chr6:134,495,725
40
Mutation frequency Chr6:134,495,725 30

30
20

20 10

0 E3 E2 E1
10
NM_005627.4
0 CCATCCTCCTCTGCTTCATGAAAGCTGTGGATG
Exon-12 11 10 9 8 7 65 4 3 21
Exon-2
one
e
lon
fied

l
ol c
tc

C
odi

Unspliced transcript Mature transcript

tan

ntr
m

Mu

Intron 1 retention Neoisoform (L)

Un

Co

1000bp Exon-1 GU AA Exon-2 Exon-1 Intron-1 Exon-2

Canonical splicing
Canonical isoform
500bp
Exon-1 GU AG Exon-2 Exon-1 Exon-2
300bp
Partial exon skipping
Neoisoform (S)
Exon-1 GU AA Exon-2 Exon-1 Exon-2
100bp Excised region
CUUUCAUGAAGCAG

124
124
D Intron
E
mutant
57
Ratio of Scaled Intron Coverage

57

4 ****
402
402
Exon
***
mutant Exon mutant
N=7
2
Intron mutant
201
201
Wild N=10
type
Wild Type
N=422
Exon-2 Exon-1 0

134174538 134174796 Kruskal−Wallis, p = 1.5e−07

F WT Mutant G Ubiquitylation
od

site M28 M33

t1
t2
t3
t4
t5
t6
t7

M1
m

1
2

3
WT
WT

WT

Mu
Mu
Mu
Mu
Mu
Mu
Mu
Un

NP_005618.2
50 KDa Δ27
SGK1 Δ32
37 KDa Exon-1 Exon-2 Exon-3
ns M69 STKc domain
NP_005618.2 ................
Δ27 ................
actin Δ32 ................
Exon-4

H W I
N od

WT-1 WT-2 WT-3 Mut-1 Mut-2 Mut-3 Exon-1 Exons 2-8

TC
m
Un
0
0

0
0

0
0

0
0

0
0

Min
60
12
24

60
12
24

60
12
24

60
12
24

60
12

60
12
24

24
0

SGK1
SGK1 ns

actin
actin

Figure 1.

960 blood® 16 SEPTEMBER 2021 | VOLUME 138, NUMBER 11 GAO et al

target of AID-mediated aberrant somatic hypermutation.6,8 How-
ever, clear hotspots were evident, especially those affecting the
splice regions either side of exon 2 (Figure 1A-B). The most fre-
quent variants affected 2 adjacent nucleotides situated at the end
of intron 1 and at the start of exon 2. These were identified in 35
and 49 patients, respectively. The exonic variant altered codon 26
(alanine); however, we hypothesized that these adjacent mutations
may both affect mRNA splicing. We generated homozygous
knockin clones by CRISPR editing of the intronic splice mutation
into 2 lymphoma cell lines (Defauw and U2932; supplemental Fig-
ure 1A) and used 5' RACE to determine the resulting SGK1 tran-
script isoforms. In both cell lines, this method revealed the
complete absence of the canonical transcript, which was replaced
by 2 neoisoforms that had not been annotated (Figure 1C; supple-
mental Figure 1B). A longer neoisoform retained the entirety of
intron 1. A shorter neoisoform excised intron 1 but used a cryptic
splice site within exon 2, leading to loss of 14 nucleotides from the
coding sequence. We then used publicly available RNA sequenc-
ing data to identify splice-mutant cases and looked for the pres-
ence of these aberrantly spliced SGK1 neoisoforms. We found
evidence of both neoisoforms in cases with the intronic SGK1
splice mutant (Figure 1D). Furthermore, intron 1 retention was
seen in cases with the adjacent exonic mutation (Figure 1D-E; sup-
plemental Table 2). This confirms that the 2 most commonly iden-
tified SGK1 variants both disrupt mRNA splicing.
The sequence of both neoisoforms altered the reading frame
and introduced premature stop codons. We were therefore sur-
prised to see increased expression of a smaller protein isoform
in edited clones when immunoblots were probed with a
C-terminal–reactive SGK1 antibody (Figure 1F). Analysis of the
nucleotide sequence of the 2 neoisoforms revealed open read-
ing frames initiated from downstream methionines (M28, M33,
and M69; Figure 1G). Taken together with the band sizes on
immunoblot analysis, this finding suggests translation of protein
isoforms that lack N-terminal 27 and 32 amino acids. These
N-terminal truncations preserve the kinase domain but remove a
ubiquitination site known to promote SGK1 degradation.16 We
determined SGK1 protein half-life in control and splice-mutant
edited clones and observed increased protein stability of both
N-terminal truncated protein isoforms (40 minutes vs .4 hours;
Figure 1H; supplemental Figure 1C). To establish whether other
nonsplicing mutations of SGK1 may also result in the same
effect we designed CRISPR gRNAs that targeted exons-1 to -7.
All 3 gRNAs targeting exon 1 led to expression of stabilized,
truncated protein isoforms that matched the size seen in the
splice-mutant CRISPR clones. In contrast, gRNAs targeting
downstream exons led to the expected depletion of the SGK1
protein (Figure 1I). This result suggests that, like the splice
mutants, nonsense and frameshift variants within exon 1 result in
translation from downstream methionines that exclude the deg-
radation domain and thereby generate stabilized SGK1 protein
isoforms. We conclude that multiple different classes of SGK1
mutation, frequently identified in DLBCL, converge on the pro-
duction of hyperstable protein isoforms.
We examined growth of the SGK1 CRISPR-edited, splice-mutant
clones using differential fluorescent labeling of control and mutant
clones pooled in competitive coculture. This method revealed a
growth advantage in splice-mutant clones over a 40-day time
course (Figure 2A). We then used a recently described experimen-
tal culture system to clone the coding sequence of the wild-type
(WT) and truncate SGK1 isoforms and express them in ex vivo cul-
tured human germinal center B cells.17,18 Neither WT nor trun-
cated SGK1 was associated with growth suppression and indeed
both were associated with a small competitive advantage (Figure
2B). Taken together, the absence of growth suppression and the
apparent competitive advantage in these 2 experimental systems
are inconsistent with a tumor-suppressor function for SGK1 in
B-cell lymphoma and support a prooncogenic effect instead.
The concept of therapeutic targeting of SGK1 in lymphoma was
previously proposed, either individually or in combination with
AKT inhibition.3,19 However, it was previously unclear how this
strategy may fit with apparent loss-of-function mutations of
SGK1. Therefore, we examined the ability of SGK1 to act redun-
dantly with AKT by overexpressing WT and truncated SGK1 neo-
isoforms in the lymphoma lines BJAB and SUDHL4, both of
which lack expression of endogenous SGK1. Overexpression of
either WT or truncated isoforms rendered cells resistant to the
AKT inhibitor AZD5363. Truncated isoforms compensated for
AKT at least as strongly as the WT isoform (Figure 2C-D; supple-
mental Figure 2A-C). The ability of canonical and truncated
SGK1 isoforms to render cells resistant to AKT inhibition was
dependent on the kinase activity of SGK1 isoforms. As such,
resistance was abrogated either by the introduction of the SGK1
kinase–inactivating K127N mutation (Figure 2D) or by exposure
to the SGK1 inhibitor GSK650394 (supplemental Figure 2D-E).
To confirm pharmacological specificity, these findings were reca-
pitulated with a different AKT inhibitor, MK2206 (supplemental
Figure 2F). The physiological existence of SGK1 isoforms trans-
lated from downstream start sites of the canonical transcript has
been noted previously, with the suggestion that shorter isoforms
may preferentially phosphorylate a distinct set of downstream
proteins, including GSK3B.20 GSK3B is known to be a direct tar-
get of both SGK1 and AKT.21 Immunoblots from transduced
BJAB and SUDHL4 cells revealed that SGK1 maintained phos-
phorylation of GSK3B in the presence of AKT inhibition. This
effect was more prominent in the presence of truncated SGSK1
isoforms (Figure 2E; supplemental Figure 2G) and abrogated by

Figure 1. SGK1 mutations lead to aberrant splicing and hyperstable protein isoforms. (A) Distribution of mutations across the SGK1 locus from 5 published
sequencing studies. The variant nucleotides depicted were identified in 5 or more cases. (B) Distribution of high-frequency variant nucleotides (identified in 10 or more
cases) at mutation hotspots flanking exon 2. The magnified region shows the position of the 2 most frequent mutations highlighted in red. (C) Agarose gel electropho-
resis showing polymerase chain reaction amplicons from 5' RACE performed on CRISPR-edited U2932 control and splice-mutant clones. The transcript neoisoform iden-
tified from Sanger sequencing of each band is shown. (D) Representative Sashimi plots from analysis of RNA sequencing data showing splicing across SGK1 intron 1.
Data from a representative case are shown for each genotype. The number of reads corresponding to each splice junction is indicated. (E) An intron 1 retention score
was calculated for each patient classified one of the genotypes. Significance was calculated using a Kruskal-Wallis test and pairwise comparisons with the Wilcoxon
rank sum test. Adjusted P values: ***P < .001; ****P < .0001. (F) Immunoblot showing expression of SGK1 protein isoforms in multiple CRISPR-edited Defauw control
and intronic splice mutant clones. The lower band is nonspecific (ns). (G) Predicted amino acid sequence from open reading frames identified in the WT and 2 aber-
rantly spliced neoisoforms. Predicted translational start sites are highlighted in yellow, the SGK1 kinase domain in pink, and the ubiquitination domain in orange. (H)
Half-life study of SGK1 protein isoforms in CRISPR-edited control or splice-mutant clones showing immunoblot at the indicated times after addition of cycloheximide.
(I) Immunoblot showing SGK1 protein isoform expression in Defauw-Cas9 cells transduced with single gRNAs targeting the indicated SGK1 exons. NTC, nontargeting
control single gRNA.

SGK1 MUTATIONS IN DLBCL blood® 16 SEPTEMBER 2021 | VOLUME 138, NUMBER 11 961
 A 1.6
SGK1 SGK1 B Primary GC B cells

GFP positive fraction (relative to day 4)

Population fraction (relative to day 0)
Wild type Splice mutant
* * * 2.0
1.4
1.2 1.5
1.0
0.8 1.0

0.6
Empty Vector
0.4 0.5 SGK1_M1
SGK1_M28
0.2 SGK1_M33
0
0
0 4 6 11 18 22 26 29 36
0 10 20 30
Time (days) Time (days)
C D
120 SGK1_M1 SGK1_M33
Empty Vector
SGK1_ M28 SGK1_M69 50
100

Apoptotic cells (% of all cells)

Live cells (% DMSO)

40
80

30
60
*** *** *** ***
40 20

20 10

0
0 0.3 0.5 1.0 3.0 0
AZD5363 concentration (µM) y

28

33

69

KD

D
pt

_K

_K
M

1_
Em

33

69
E

M
DMSO AZD5363

M
F
y

y
pt

pt
28

69

28
33

69
33
1

1
em

em
M

M
M
M

M
M

150
GSK3B (ser9)
Live cells (% DMSO)

actin
100

GSK3B (total)
**
50
actin

MYC 0
AZD5365 (µM) 1.0 3.0 10 0 0 0 3.0 3.0 3.0
GSK650394 (µM) 0 0 0 1.0 3.0 10 1.0 3.0 10
actin

Figure 2. Increased SGK1 expression promotes cell growth and AKT independence. (A) CRISPR-edited control or splice-mutant Defauw clones were labeled with
GFP and pooled for competitive growth. The relative proportion of control and mutant clones is shown over a 40-day time course. Data reflect 3 separate pairings of 3
WT and 3 mutant clones. Significance was calculated by paired Student t test. *P < .05. (B) Primary human germinal center B cells were immortalized with BCL6-2A-
BCL2 and then transduced with cDNAs encoding canonical or truncated SGK1 isoforms. Constructs encoding SGK1 isoforms are named by the position of the initiating
methionine. The frequency of cells transduced with each SGK1 isoform was quantified by flow cytometry at intervals of >30 days and normalized to day 4. (C) Cell via-
bility measured by CellTiter-Glo after a 5-day treatment with the AKT inhibitor AZD5363 in BJAB cells transduced with control, canonical (M1) or N-terminal truncated
(M28, M32, and M69) SGK1 isoforms. The figure shows an average of 4 independently conducted experiments; error bars represent standard error of the mean (SEM).
(D) BJAB cells were transduced with the indicated canonical or truncated SGK1 isoforms, with or without the K127N kinase-dead (KD) mutation. Apoptosis was quanti-
fied by intracellular staining for caspase-3 and cleaved PARP 3 days after treatment with 500 nM AZD5363. Data show average and SEM of 3 separate experiments.
Significance compared with the empty vector control was calculated by analysis of variance (ANOVA) and Dunnett’s multiple comparisons test. ***P < .001. (E) Immu-
noblot stained for phospho- and total GSK3B. Lysates are from BJAB cells stably transduced with the indicated canonical, WT (M1), or N-terminal truncated (M28,
M32, and M69) SGK1 isoforms and treated with AZD5363 (500 nM) or dimethyl sulfoxide (DMSO) for 24 hours. Data are representative of 3 independent experiments.
(F) Defauw cells were treated with the indicated concentration of AZD5363 and the SGK1 inhibitor GSK650394, either individually or in combination. Cell viability was
measured by CellTiter-Glo. Data show average and SEM of 3 separate experiments. Significance compared with DMSO control was calculated by ANOVA and Dun-
nett’s multiple comparisons test. **P < .01.

962 blood® 16 SEPTEMBER 2021 | VOLUME 138, NUMBER 11 GAO et al

a K127N kinase–inactivating mutation of SGK1 (supplemental
Figure 2H). SGK1-induced changes in GSK3B phosphorylation
were associated with corresponding changes in expression of
MYC, a known target of GSK3B (Figure 2E). Other targets of
either canonical or truncated SGK1 isoforms in the setting of lym-
phomagenesis remain to be determined. However, the findings
herein are evidence that stabilized, truncated SGK1 neoisoforms
retain kinase activity, supporting the conclusion that many SGK1
mutations found in DLBCL lead to gain, not loss, of function. The
findings also suggest that some AKT inhibitor-resistant lympho-
mas may be rendered sensitive by dual inhibition with AKT and
SGK1 inhibitors. Indeed, SGK1 inhibition sensitized the SGK1-
expressing cell line Defauw to AKT inhibition (Figure 2F).
members of the flow cytometry core for advice and support in flow
cytometry.
This work was supported by the National Institute for Health Research
(NIHR) Cambridge Bioresearch Center (BRC) Cell Phenotyping Hub
and the NIHR Cambridge BRC (BRC-1215-20014) and by core fund-
ing from the UK Medical Research Council (MC_UU_12022/10) (S.S).
D.H. was supported by a Clinician Scientist Fellowship and is cur-
rently supported by a Cancer Research UK (CRUK) Senior Research
Fellowship (RCCFEL\100072). Research in the D.J.H. laboratory is
supported by the Medical Research Council (MR/M008584/1) and the
Kay Kendall Leukaemia Fund (KKL1144). The D.J.H. laboratory
receives core funding from Wellcome (203151/Z/16/Z) and the Medi-
cal Research Council (MRC) to the Wellcome-MRC Cambridge Stem
Cell Institute and from the CRUK Cambridge Centre (A25117).

We recognize that SGK1 has not emerged as a lymphoma-
essential gene in recent lymphoma CRISPR screens.2,22 This fact
may reflect redundancy with SGK3 or with other related kinases,
such as AKT. Alternatively, CRISPR screening data may be compli-
cated by the inclusion of gRNAs that target SGK1 exon 1, leading
to increased protein expression. Finally, the oncogenic require-
ment of SGK1 may be restricted either to a specific stage of B cell
differentiation or to a specific molecular subtype of DLBCL. Nota-
bly, there is currently no cell line model of the ST2 molecular sub-
type of DLBCL; therefore, the requirement for SGK1 has not been
tested in the subtype in which its mutation is most frequently
found. A lymphoma-promoting role for SGK1 in the ST2 molecular
subtype is plausible, because SGK1 expression is known to be
positively regulated by STAT3 activity.19 Indeed, both control and
splice mutant clones showed elevated protein expression when
STAT3 activation was induced with interleukin-21 (supplemental
Figure 2I). Notably, JAK/STAT signaling is activated in the ST2
subtype by mutation of SOCS1 and DUSP2 and by activating
mutation of STAT3 itself.4,5 Therefore, within the ST2 subtype,
diverse genetic alterations may converge directly or indirectly on
the upregulated expression of SGK1.
The views expressed are those of the authors and not necessarily
those of the NIHR or the Department of Health and Social Care.
Authorship
Contribution: J.G. and E.S. designed and conducted the experiments
and analyzed the data; K.M. and Z.U. conducted the experiments; J.A.K.
and I.W. analyzed the RNA sequencing data with supervision from
S.A.S.; and D.J.H. obtained the funding, designed the experiments, ana-
lyzed the data, directed the research, and wrote the manuscript with con-
tributions from J.G.
Conflict-of-interest disclosure: D.J.H. has received research funding from
Gilead Sciences and Astra Zeneca. The remaining authors declare no
competing financial interests.
ORCID profiles: D.J.H., 0000-0001-6225-2033; J.A.K., 0000-0003-0369-
0329; S.A.S., 0000-0003-1046-0601.
Correspondence: Daniel J. Hodson, Wellcome-MRC Cambridge Stem
Cell Institute, Jeffrey Cheah Biomedical Centre, Cambridge CB2 0AW,
United Kingdom; e-mail: djh1002@cam.ac.uk.

Overall, these results challenge the widely held assumption that

SGK1 mutations lead to loss-of-function of a tumor suppressor in
DLBCL. They reveal instead how deleterious and splice mutations
lead to increased expression of truncated, hyperstable protein iso-
forms that retain kinase activity. Finally, they provide impetus to
identify downstream targets of SGK1 and to explore the potential
for SGK1 inhibition as therapy in specific subtypes of DLBCL .
Footnotes
Submitted 15 December 2020; accepted 7 May 2021; prepublished
online on Blood First Edition 14 May 2021. DOI 10.1182/
blood.2020010432.
Original data will be made available in response to an e-mail request to
the corresponding author.
The online version of this article contains a data supplement.

Acknowledgments There is a Blood Commentary on this article in this issue.

The authors thank Jessica Bewick, Alice Mitchell, and Nicholaas Jonas
(ENT Department, Addenbrooke’s Hospital, Cambridge, United King-
dom) for assistance in the collection of primary tonsil tissue; Kay
Elston, Jane Price, and Joanna Baxter (Cambridge Blood and Stem
Cell Bank) for collection and storage of primary tonsil tissue, and all
The publication costs of this article were defrayed in part by page charge
payment. Therefore, and solely to indicate this fact, this article is hereby
marked ”advertisement” in accordance with 18 USC section 1734.

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