Onco a ge 90622
www.impac jou nals.com/onco a ge
www.impac jou nals.com/onco a ge / Onco a ge , 2017, Vol. 8, (No. 53), pp: 90622-90623
Mul i ace ed CK2 in malignan and heal hy T cells
Sé gio T. Ribei o, João T. Ba a a and B uno Sil a-San os
Among kinases ha suppo he su i al and
u no e o umo cells, he se ine/ h eonine p o ein kinase
CK2 has been shown o be equen ly o e exp essed o
hype ac i a ed in solid and hema ological malignancies.
Ou p e ious wo k on T-cell acu e lymphoblas ic leukemia
(T-ALL) showed ha CK2 main ains leukemia cell
iabili y by phospho yla ing and he eby inac i a ing he
umo supp esso PTEN, which esul s in hype ac i a ion
o PI3K/AKT signaling [1]. We also demons a ed he
po en ial o using he clinical-g ade CK2-speci ic chemical
inhibi o , CX-4945 (Silmi ase ib), agains p ima y T-ALL
cells [2]. We ha e now [3] ex ended hese indings o he
a e (<10% o all cases) o m o T-ALL ha de i es om
he ans o ma ion o hymocy es belonging o he γδ
T-cell lineage [4].
γδ T cells de elop in he hymus om p ogeni o s
common o he αβ T-cell lineage, and cons i u e a small
popula ion (1-5%) o he ci cula ing T lymphocy e pool
o heal hy humans. In leukemia, malignan γδ T cells
cause he γδ T-ALL sub ype ha p esen s wi h dis inc i e
clinical ea u es [4]. Howe e , he molecula mechanisms
ha suppo γδ T-ALL homeos asis and p og ession
emain poo ly unde s ood.
In ou mos ecen s udy, we iden i y CK2 as a no el
de e minan o γδ T-ALL cell su i al [3]. Consis en wi h
p e ious T-ALL da a [1-2], CK2 p omo ed γδ T-ALL
cell su i al pa ly ia AKT signaling, as demons a ed
by he nega i e e ec s o CX-4945 on PTEN and AKT
phospho yla ion; he impac o he AKT inhibi o MK-
2206; and he pa ial escue o CX-4945-induced apop osis
upon ec opic exp ession o a cons i u i ely ac i e AKT
iso o m [3]. Rema kably, howe e , p ima y γδ T-ALL
cells we e clea ly mo e dependen on CK2 han αβ T-ALL
cells, wi h signi ican ly highe CK2 ac i i y and sensi i i y
o CX-4945. Acco dingly, CX-4945 ea men inhibi ed
umo p og ession and dissemina ion in a xenog a
model o γδ T-ALL, hus suppo ing CK2 inhibi ion as a
he apeu ic app oach in γδ T-ALL.
In e es ingly, ou s udy also e ealed an
unan icipa ed ole o CK2 in con olling he su i al
o no mal γδ hymocy es [3], which con as ed wi h ou
p e ious indings on heal hy αβ hymocy es [1]. Thus, γδ
hymocy es p esen ed inc eased CK2 ac i i y (which was
u he up egula ed upon TCR s imula ion) han hei αβ
coun e pa s; and, unlike hese, we e highly suscep ible o
CX-4945-induced apop osis. This sugges s ha a possible
unwan ed side e ec o CX-4945 ea men in cance
pa ien s may be he deple ion o heal hy γδ T cells ha
p o ide an i- umo immune su eillance [5].
O no e, s udies in mice ha e sugges ed ha CK2 is
also in ol ed in he supp essi e unc ion o CD4+ Foxp3+
egula o y T cells agains alle gy-p omo ing Th2 cells
[6]; and in naï e CD4+ T cell di e en ia ion in o Th2 o
Th17 cells [7]. Thus, CK2 inhibi ion may impac on o he
p o ec i e (agains in ec ion) o pa hogenic (alle gic o
au o-in lamma o y) immune esponses.
The mechanisms o egula ion o CK2 ac i i y
emain la gely unknown, wi h e y ew s udies
demons a ing he modula ion o CK2 ac i i y by
ex acellula ac o s. Ou esul s show ha CK2 ac i i y
can be enhanced by TCR and CD27 (co)s imula ion in γδ
T cells [3]. In a di e en s udy, we ha e also demons a ed
ha IL-7/IL-7R s imula ion up egula es CK2 ac i i y,
which is equi ed o maximal IL-7R- igge ed JAK1/
STAT5 and AKT signaling, and consequen p o-leukemia
e ec s, in T-ALL cells [8]. The e o e, majo molecula
cues in T cell de elopmen may con e ge in inc easing
(by ye unclea mechanisms) CK2 ac i i y in heal hy and
malignan hymocy es. As such, ou s udies collec i ely
suppo he use o CK2 inhibi o s (e.g. CX-4945) as
pu a i e he apy o bo h αβ and γδ T-ALL.
B uno Sil a-San os: Ins i u o de Medicina Molecula ,
Faculdade de Medicina, Uni e sidade de Lisboa, Lisboa,
Po ugal
Co espondence o: B uno Sil a-San os, email bssan os@me-
dicina.ulisboa.p
João T. Ba a a: Ins i u o de Medicina Molecula , Faculdade
de Medicina, Uni e sidade de Lisboa, Lisboa, Po ugal
Co espondence o: João T. Ba a a, email joao_ba a a@
medicina.ulisboa.p
Keywo ds: p o ein kinase CK2, γδ T lymphocy es, T-cell acu e
lymphoblas ic leukemia
Recei ed: Sep embe 20, 2017
Published: Oc obe 09, 2017
REFERENCES
1. Sil a A, e al. J Clin In es . 2008; 11:3762-74.
2. Buon empo F, e al. Leukemia. 2014; 3:543-53.
3. Ribei o ST, e al. Leukemia. 2017; 31:1603-10.
4. Ma os DM, e al. Haema ologica. 2005; 90:264-6.
Edi o ial
Onco a ge 90623
www.impac jou nals.com/onco a ge
5. Sil a-San os B, e al. Na Re Immunol. 2015; 15:683-91.
6. Ulges A, e al. Na Immunol. 2015; 16:267-75.
7. Ses e o CM, e al. J Immunol. 2012; 189:2918-30.
8. Melão A, e al. Haema ologica. 2015; 101:1368-79.
Copy igh : Ribei o e al. This is an open-access a icle dis ibu ed
unde he e ms o he C ea i e Commons A ibu ion License 3.0
(CC BY 3.0), which pe mi s un es ic ed use, dis ibu ion, and e-
p oduc ion in any medium, p o ided he o iginal au ho and sou ce
a e c edi ed.