Multifaceted CK2 in malignant and healthy T cells

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.