Correspondence: Lorenzo Leoncini E-mail: leoncinil@unisi.it
SUMMARY
Since its discovery in the 1970’s, MYC oncoprotein has been continuing to fascinate WKHVFLHQWLÀFZRUOGDQGWKHUHLVDJURZLQJLQWHUHVWLQWKHUROHRIMYC in the genesis and prognosis of cancer.
,QLWLDOO\MYCZDVLGHQWLÀHGDVWKHFHOOXODUKRPRORJXHRIWKH0& WUDQVIRUPLQJDYLDQ UHWURYLUXV 6KRUWO\ KHUHDIWHU DGGLWLRQDO UHODWHG VHTXHQFHV ZHUH LGHQWLÀHG VXJJHVWLQJ that MYCPLJKWEHSDUWRIDODUJHUIDPLO\RIJHQHV
7KHFRQVWHOODWLRQRIMYC HIIHFWVRQJHQHVLQYROYHGLQSUROLIHUDWLRQKDVOHGWRWKHFRQ-cept of MYCGULYHQO\PSKRPDVWKDWLQFOXGH%XUNLWWO\PSKRPD %/ GLIIXVHODUJH%FHOO O\PSKRPD '/%&/ DQG O\PSKRPDV WKDW VKDUH PRUSKRORJLF IHDWXUHV RI '/%&/ DQG %/ RIÀFLDOO\ WHUPHG %FHOO O\PSKRPD XQFODVVLÀDEOH ZLWK IHDWXUHV LQWHUPHGLDWH EH-WZHHQ'/%&/DQG%/ %&/8 2WKHUO\PSKRPDVVKRZLQJ0<&RYHUH[SUHVVLRQFRPSULVHV 3ODVPDEODVWLFO\PSKRPDDQG3ODVPDF\WRPD'RXEOHKLWWULSOHKLWO\PSKRPDVDQG$Q-DSODVWLFO\PSKRPDV.LQDVHSRVLWLYH/DUJH%FHOO/\PSKRPD MYC DEHUUDWLRQVFDQEHGHWHFWHGE\VWDQGDUGF\WRJHQHWLFVLQWHUSKDVHÁXRUHVFHQFH in situ K\EULGL]DWLRQ ),6+ FRPSDUDWLYHJHQRPLFK\EULGL]DWLRQDQGPRVWUHFHQWO\LPPX-QRKLVWRFKHPLVWU\%\FRPSDULQJH[SUHVVLRQSURÀOHVRIMYC JHQHUHDUUDQJHPHQWDQG 0<&SURWHLQH[SUHVVLRQKDVFDPHXSWKDWMYC JHQHUHDUUDQJHPHQWVGRQRWQHFHV-VDULO\FRUUHODWHZLWK0<&SURWHLQH[SUHVVLRQ,QIDFWE\DSSO\LQJLPPXQRLVWRFKHPLVWU\ WKHIUHTXHQF\RI0<&SURWHLQH[SUHVVLRQDSSHDUVPXFKKLJKHUWKDQZKDWLVGHWHFWHG E\),6+VWDQGDUGPHWKRG7KHUHIRUHQRZDGD\VWKHNH\SUREOHPLQWKHKHPDWRSDWKRO-RJ\ÀHOGLVWRGHÀQHWKHFOLQLFDOLPSDFWRIWKHGRXEOHH[SUHVVRUO\PSKRPDVWDWXV7KH XSGDWHG:RUOG+HDOWK2UJDQL]DWLRQ :+2 RIWXPRXUVRIKHPDWRSRLHWLFDQGO\PSKRLG WLVVXHVDVVHVWKDWWKHVWDWXVRIGRXEOHRUWULSOHO\PSKRPDVKRXOGUHO\RQO\RQPROHFXODU ELRORJ\ÀQGLQJVDQGQRWRQLPPXQRKLVWRFKHPLVWU\UHVXOWV
Correlation between MYC gene
rearrangement and MYC protein
expression suggests that MYC regulation
is more complex than previously known
Maria Raffaella Ambrosio1, Giuseppe Lo Bello1, Aurora Barone2,Raffaella Santi2, Lorenzo Leoncini1
16HFWLRQRI3DWKRORJ\'HSDUWPHQWRI0HGLFDO%LRWHFKQRORJLHV8QLYHUVLW\RI6LHQD,WDO\ $]LHQGD2VSHGDOLHUD8QLYHUVLWDULD&DUHJJL8QLWjRSHUDWLYDGL$QDWRPLD3DWRORJLFD)LUHQ]H,WDO\
Key words: MYC gene dysregulation; MYC protein expression; Burkitt lymphoma.
ZZZ INTRODUCTION
The iconic history of the MYC oncop-rotein encompasses three decades RILQWHQVHVFLHQWLÀFGLVFRYHU\7KHUHLV no question that MYC has been a pi-RQHHU DGYDQFLQJ RXU LQVLJKW LQWR WKH
molecular basis of cancer, as well as IXQFWLRQLQJ DV D PRGHO RI VHYHUDO GL- YHUVHELRORJLFDOSURFHVVHVDQGUHJXOD-tory mechanisms.
By analyzing all the published articles on MYC, two major themes emerge: ÀUVW WKH ÀQHWXQHG UHJXODWLRQ DQG QXPHURXV DFWLYLWLHV RI 0<& LQ QRUPDO cells; second, the role of MYC as on-coprotein when its regulation is lost (1). Identification of MYC
,QWKHODWH ·VDQDYLDQDFXWHOHX- NHPLDYLUXV 0& ZDVVKRZQWRSUR-mote a spectrum of malignancies, in-cluding myelocytomas, sarcomas and carcinomas.
This ability to induce carcinomas was of particular interest. The transforming VHTXHQFH RI 0& ZDV LGHQWLÀHG DV YP\F DQG QDPHG P\HORF\WRPDWR-VLVIRUDUHVXOWDQWOHXNHPLDYP\FZDV found to present in the cells as a 110 N'DYJDJP\FIXVLRQ
Consistent with the notion that onco-JHQHVFRXOGEHVWROHQE\UHWURYLUXVHV WKHFHOOXODUKRPRORJXHZDVLGHQWLÀHG soon after in normal cells from many VSHFLHV7KHGLVFRYHU\RI0<&IXUWKHU reinforced the startling realization that oncogenic transformation could be FDXVHGE\WKHDFWLYDWLRQRIDFHOOXODU JHQH
),*85( The structural domains of human MYC.
The MYC family of transforming oncoproteins
MYCZDVÀUVWLGHQWLÀHGDVWKHFHOOXODU
KRPRORJXHRIWKH0& WUDQVIRUPLQJ DYLDQUHWURYLUXV$VFKHPDWLFUHSUHVHQ-tation of human MYC is presented in )LJXUH Soon after, additional related VHTXHQFHV ZHUH LGHQWLÀHG VXJJHVW-ing that MYC might be part of a larger family of genes. Two family members, MYCN and 0<&/ZHUHLGHQWLÀHGDV DUHVXOWRIWKHLUDPSOLÀFDWLRQVLQQHXUR- EODVWRPDDQGOXQJFDQFHUUHVSHFWLYH-ly (6-11). While there is a clear role for all family members in tumorigenesis, there are some important differences that exist between family members. Spe-FLÀFDOO\ 0<&/ consistently promotes transformation to a lesser extent than the other two family members, and to date the mechanisms underlying this UHPDLQDTXHVWLRQLQWKHÀHOGMYCN, on the other hand, has been shown to be functionally interchangeable with
MYC
LQGHYHORSPHQWWKURXJKWKHJHQ-eration of a knock-in mouse model (6). MYC: structure and functions
$OO WKH JHQHV EHORQJLQJ WR WKH MYC proto-oncogene family are expressed LQPDPPDOV$IRUWKJHQH%MYC, en-FRGHVDSURWHLQWKDWVKRZVVLJQLÀFDQW homology to the N-terminus, but lacks
essential domains in the C-terminus of the other MYC proteins, and its biology is poorly understood. The MYC gene is located on the human chromosome T DQG LW FRQVLVWV LQ WKUHH H[RQV 7UDQVODWLRQDWWKH$8*VWDUWFRGRQQX-cleotide in the second exon produces DPDMRU DPLQRDFLG0<&SURWHLQ N'D $OWHUQDWLYH WUDQVODWLRQ LQLWLD-tion start sites result in both longer and shorter forms of the protein.
$ORQJHUSRO\SHSWLGHRIN'DUHVXOWV IURP WUDQVODWLRQ LQLWLDWHG FRGRQV XSVWUHDPRIWKH$8*DWD&8*FRGRQ H[RQ DQG WKH VKRUWHU RQH N'D polypeptide, results from an internal translation initiated.
The MYC protein is O-linked glycosylat-ed and phosphorylatglycosylat-ed and these PRGLÀFDWLRQV PD\ DOWHU WKH SURWHLQ KDOIOLIH$VVXFKLWLVLPSRUWDQWWRQRWH
that MYC P51$ DQG SURWHLQ KDYH D
YHU\VKRUWKDOIOLIH PLQ DQGDUH tightly regulated. MYC gene encodes for a transcription factor of the basic helix-loop-helix leucine zipper (b-HLH-LZ) superfamily. Traditionally the MYC protein is functionally referred to a N-terminal domain (NTD) and a C-ter-minal domain. The N-terC-ter-minal, which is GHÀQHGDVDPLQRDFLGVDQGWKH &WHUPLQDO GHÀQHG DV UHVLGXHV PDWFKUHVSHFWLYHO\WRWKH1WHUPL-QDOWUDQVDFWLYDWLRQGRPDLQ 7$' DQG &WHUPLQDO'1$ELQGLQJDQGEDVLFUH-gion/helix-loop-helix/leucine-zipper (BR/HLH/LZ) domain (1).
The N-terminus of MYC is the major reg-ulatory region responsible for assembly of the transcriptional machinery. With-in the N-termWith-inus there are three highly FRQVHUYHG HOHPHQWV NQRZQ DV MYC boxes I-III which, together with the &WHUPLQDO E+/+/= GHÀQH WKH 0<& family of proteins. Of these, MYC box
I (MBI, from approximately amino ac-LGV DQG 0<& ER[ ,, 0%,, IURP DSSUR[LPDWHO\ DPLQR DFLGV FRQWDLQ VHTXHQFHV KLJKO\ FRQVHUYHG among the different MYC family of SURWHLQV WKURXJKRXW HYROXWLRQ 7KHVH two regions appear to be particularly LPSRUWDQWIRUWKHWUDQVFULSWLRQDFWLYLW\ of MYC; in fact, deletion of either MBI or MBII, diminishes the transcriptional DFWLYDWLRQSRWHQWLDOIROGUHVSHF-WLYHO\
6SHFLÀFDOO\ DOWKRXJK 0%, LV UHTXLUHG IRUJHQHDFWLYDWLRQGHOHWLRQRIWKLVUH-gion only partially abolishes the trans-forming ability of MYC while an MBII deletion, which is essential for the abil-ity of MYC WRWUDQVIRUPGULYHFHOOSUR-OLIHUDWLRQ DQG DFWLYDWH FHUWDLQ WDUJHW genes, completely abolished it. MYC ER[,,LVQRWLQYROYHGLQWKHELQGLQJRI 0<&WR0D[RUWR'1$EXWLVUHTXLUHG IRU DFWLYDWLRQ DQG UHSUHVVLRQ RI PRVW but not all, MYC target genes. Recent-O\DWKLUGFRQVHUYHGUHJLRQRI0<&KDV been described, MYC box III (MBIII), that plays a role in transformation, lym-phomagenesis and apoptosis.
MYC biological activities Cell cycle and differentiation
7KHUHZHUHVHYHUDOOLQHVRIHYLGHQFHWR suggest that MYC might play a role in cell cycle progression. Ectopic expres-sion of MYC promotes growth factor LQGHSHQGHQW SUROLIHUDWLRQ 1RW unrelated to the ability to promote cell cycle progression, MYC expres-sion also blocks differentiation. It was demonstrated by multiple groups and through a number of models that MYC down-regulation is essential for cells to exit the cell cycle and undergo differ-entiation. These abilities to promote cell proliferation and block
differenti-DWLRQ KDYH QDWXUDO DVVRFLDWLRQV ZLWK tumorigenesis and are features of ag-JUHVVLYHGLVHDVH
$SRSWRVLV
The ability of MYC to promote apop- WRVLVSURYLGHVDEXLOWLQVDIHW\PHFKD-nism to protect against inappropriate proliferation as a consequence of de-UHJXODWHG0<& 7KLVÀQGLQJDOVR shed considerable light on the model of oncogene cooperation and how DQDQWLDSRSWRWLFSURWHLQVXFKDV%&/ could cooperate with MYC to promote RQFRJHQHVLV 0RUHRYHUGHUHJ-XODWLRQRI0<&ZDVVKRZQWRDFWLYDWH WKHWXPRUVXSSUHVVRUSWKURXJKWKH XSUHJXODWLRQ RI $5) $ ORVV RI either of these tumor suppressors ac-celerated tumorigenesis in mouse
models of oncogenic MYC
)XUWKHU 0<& LV DOVR DEOH WR SURPRWH DSRSWRVLV WKURXJK SLQGHSHQGHQW PHFKDQLVPV E\ LQÁXHQFLQJ WKH EDO-ance between pro- and anti- apoptot-LFSURWHLQVLQWKHFHOO
Transcriptional activation
The C-terminus of MYC was shown to contain both a helix-loop-helix (HLH) DQGDOHXFLQH]LSSHU /= GRPDLQ WRZKLFKD0<&SDUWQHUFDQELQGV 0$; 0<& DVVRFLDWHG IDFWRU ; 0$;ZDVVKRZQWREHDFRQVWDQWDQG obligate partner for MYC, with consis-tent and abundant expression in both proliferating and quiescent cells, which was not altered in response to extra-FHOOXODUVWLPXOL,WLVKRZHYHULPSRUWDQW WRQRWHWKDW0$;DOVRIRUPVKHWHURGL-PHUVZLWKPHPEHUVRIWKH0;'IDPLO\ ZKLFKWKHUHE\SURYLGHVDQDGGLWLRQDO PHFKDQLVP WR UHJXODWH 0<& DFWLYLW\ LQWKHFHOO ,QQRQWUDQVIRUPHG cells, the MYC protein appears to
inte-JUDWH HQYLURQPHQWDO VLJQDOV LQ RUGHU WRPRGXODWHDGLYHUVHDQGVRPHWLPHV RSSRVLQJ JURXS RI ELRORJLFDO DFWLY-ities, including proliferation, growth, apoptosis, energy metabolism and dif- IHUHQWLDWLRQ0<&SURWHLQOHYHOVDUHLQ- GXFHGRUVXSSUHVVHGE\YLUWXDOO\DOOVLJ-QDOOLQJ FDVFDGH EHDULQJ SUROLIHUDWLYH DQGDQWLSUROLIHUDWLYHFXHVUHVSHFWLYH-ly. Mitogen stimulation induces MYC as an immediate-early response gene, whose expression is essential and suf-ÀFLHQW IRU WKH *6 SURJUHVVLRQ MYC DOVR SOD\V D UROH LQ *0 WUDQVLWLRQ making it one of the key players in cell F\FOH UHJXODWLRQ $EQRUPDO RU HFWR-SLFRYHUH[SUHVVLRQRI0<&LQSULPDU\ FHOOV DFWLYDWHV D SURWHFWLYH SDWKZD\ WKURXJK WKH LQGXFWLRQ RI SS$5) DQG WKH SGHSHQGHQW FHOO GHDWK pathway. Hence, normal cells that RYHUH[SUHVV0<&DUHHOLPLQDWHGIURP the host organism through apoptosis, thereby protecting the organism from lethal neoplastic changes.
Transcriptional regulation
0<& FDQ ERWK DFWLYDWH DQG UHSUHVV transcription of its target genes. MYC-0D[ KHWHURGLPHUV DFWLYDWH WUDQVFULS-tion by binding to E-box elements. The '1$ ELQGLQJ RI 0<& DQG 0D[ FRP-plexes is mediated by amino terminal DPLQRDFLGVRIF0<& 7$' 'H-OHWLRQV ZLWKLQ WKH 1WHUPLQDO 7$' FDQ greatly affect or abrogate the biologi- FDOIXQFWLRQRI0<&DVLWVWUDQVDFWLYD-WLRQ SRWHQWLDO 7KH DFWLYDFDOIXQFWLRQRI0<&DVLWVWUDQVDFWLYD-WLRQ LQYROYHV WKH UHFUXLWPHQW RI PXOWLSOH FRDFWLYD-tors and protein complexes to E-box HOHPHQWV &RDFWLYDWRUV LQFOXGH WKH 0HGLDWRU FRPSOH[ 3RVLWLYH 7UDQVFULS-WLRQ (ORQJD7UDQVFULS-WLRQ )DFWRU E 37()E WKH $73DVHV 7,3 DQG 7,3 DQG KLVWRQH acetyltransferases such as
CREB-bind-LQJSURWHLQ &%3 DQGS*&1DQG 7,3 2I QRWH *&1 DQG 7,3 DUH bound to MYC indirectly through the 755$3 DGDSWRU SURWHLQ WKDW LQWHUDFWV ZLWK 0<& ER[ ,, 755$3 DOVR UHFUXLWV WKH S KLVWRQHH[FKDQJH SURWHLQ WR0<&$QRWKHUZD\IRU0<&WRDF-WLYDWH WDUJHW JHQHV LV E\ LQWHUDFWLRQ
ZLWK ( XELTXLWLQ OLJDVH 6&)6.3 6.3
ZKLFKUHFUXLWVFRPSRQHQWVRIWKH$3,6 complex to E-box sequences. Trans-DFWLYDWLRQ E\ 0<& LV DQWDJRQL]HG E\ Mad-Max and Mnt-Max heterodimers, which repress transcription by recruit-ing histone deacetylase complexes +'$&V WKURXJK WKH DGDSWRU SURWHLQ 6,1 51$SRO,,DQG6$3
Interestingly, only a minority of the sites to which MYC and Max are bound in
vivo KDYH D FRQVHQVXV &$&*7*
VH-quence. Indeed, MYC-Max heterodi-mers are able to recognize non canon-LFDO VLWHV YDULDWLRQV RI WKH FDQRQcanon-LFDO (ER[FRQWDLQLQJFRUH7*RU&*GLQX-cleotides. In addition, nucleotides im-PHGLDWHO\ÁDQNLQJWKH(ER[DVZHOODV PHWK\ODWLRQ RI &S* ZLWKLQ WKH (ER[ can affect MYC-Max binding. In those cases, is possible that MYC and Max are recruited to non-consensus binding sites through the interaction with other transcription factors. One example is offer by Miz1, which can recruit MYC and Max to core promoter sequence WKDW ODFN D &$&*7* VHTXHQFH 7KH association Max-MYC allows the in-teractions with a number of addition-al transcription factors and co-factors that modulate transcriptional acti-YDWLRQ2QHLV75$$3, which is a core VXEXQLWRIWKH7,3DQG*&1KLVWRQH DFHW\OWUDQVIHUDVH +$7 FRPSOH[HV 0<& UHFUXLWV +$7 DFWLYLW\ WR LWV WDUJHW genes and the recruitment depend on the integrity of MYC box II. Inhibition of
75$$3V\QWKHVLVEORFNV0<&PHGLDWHG oncogenesis, establishing an essential UROHIRU75$$3LQ0<&DFWLYLW\75$$3 is also part of a complex containing WKHS($ELQGLQJSURWHLQZKLFKLV GHYRLGRI+$7DFWLYLW\VXJJHVWLQJWKDW 0<&75$$3LQWHUDFWLRQKDVRWKHUUROHV in additional roles in addition to recruit-LQJRI+$7DFWLYLW\7ZRRWKHUSURWHLQV bind to MYC box II independently of 75$$3 WKHVHDUH7,3DQG7,3 , two KLJKO\ FRQVHUYHG KH[DPHULF $73DVHV ERWKLQYROYHGLQVHYHUDOFKURPDWLQUH-modelling complexes. Both proteins KDYH $73 K\GURO\VLQJ DFWLYLW\ DV ZHOO DV VXVSHFWHG KHOLFDVH DFWLYLW\ DQG KDYH EHHQ VKRZQ WR EH UHTXLUHG IRU the foci formation by MYC and Ras in a primary co-transformation assay. MYC box II is required for interaction ZLWK 6.3 RI WKH ( XELTXLWLQ OLJDVH
6&)6.3
DQG0<&UHFUXLWV6.3WRLWVWDU-get genes in vivo5HFUXLWPHQWRI63. LV UHTXLUHG IRU WKH WUDQVDFWLYDWLRQ RI VHYHUDO0<&WDUJHWJHQHV,QWHUHVWLQJ-ly, not all MYC target genes require the LQWHJULW\ RI 0<& ER[ ,, IRU DFWLYDWLRQ suggesting that there are other mech-DQLVPVRI0<&GHSHQGHQWDFWLYDWLRQ In the past MYC has been considered D´SHUPLVVLYHIDFWRUµVWLPXODWLQJJHQH DFWLYLW\ E\ FUHDWLQJ D FKURPDWLQ HQ-YLURQPHQW WKDW LV FRQGXFLYH IRU JHQH induction. It has been recently shown WKDW0<&GULYHQWUDQVFULSWLRQDOUHSUHV-VLRQLVFULWLFDOIRULWVRQFRJHQLFDFWLYLW\ +RZHYHUOHVVLVNQRZQDERXWKRZ0<& UHSUHVVHVWUDQVFULSWLRQ5HFHQWÀQGLQJV VXJJHVWWKHLQYROYHPHQWRI'1$PHWK-ylatransferases enzymes (DNMTs) and KLVWRQH GHDFHW\ODVH +'$& DV SRV-sible cofactors in the MYC-mediated WUDQVFULSWLRQUHSUHVVLRQ'1$PHWK\OD-WLRQDW&S*GLQXFOHRWLGHVLVWKHPDMRU HSLJHQHWLF PRGLÀFDWLRQ LQ PDPPDOV
and is known to be associated with transcriptional repression. The three DFWLYH '1$ &S* PHWK\ODWUDQVIHUDVHV LGHQWLÀHGLQPDPPDOVDUH'107'1-07D DQG E :KHUHDV '1LGHQWLÀHGLQPDPPDOVDUH'107'1-07D DQG EKDYHEHHQVKRZQWREHUHTXLUHGIRU de novo methylation, DNMT1 appears to function primarily as a maintenance methylatransferase, restoring methyl-DWHG F\WRVLQH IROORZLQJ '1$ UHSOLFD-WLRQ 6HYHUDO VWXGLHV KDYH VKRZQ WKDW DNMTs can act as corepressors to si-lence gene expression that maintain chromatin in a compacted and silent state. Indeed, it was recently demon-strated the ability of MYC to repress the transcription through recruitment RI'107DWRWKH0<&0L]FRPSOH[ indicating that MYC-dependent gene repression could at least partly be me-diated by methylation of its target pro-moters (1).
Novel biological activities
In recent years, additional biological DFWLYLWLHVRI0<&KDYHEHHQFKDUDFWHU-ized. The renewed interest in the War-burg effect and tumor cell metabolism has highlighted a new role for MYC. In addition to stimulating mitochondrial ELRJHQHVLV RQFRJHQLF OHYHOV RI 0<& KDYH EHHQ VKRZQ WR SURPRWH PLQRO\VLV 7KLV LQFUHDVHG JOXWD-mine metabolism fuels cell growth and proliferation, which are essential for tu- PRUFHOOVWRWKULYH,WKDVEHHQVXJJHVW-ed that tumor cells become addictPRUFHOOVWRWKULYH,WKDVEHHQVXJJHVW-ed WRJOXWDPLQHZKLFKPD\SURYLGHRS-SRUWXQLWLHVIRUWKHUDSHXWLFLQWHUYHQWLRQ 0RUHRYHUMYC gene can induce senescence in the context of the loss
of other genes such as WRN or &'.
7KHDELOLW\RIMYC to block dif-ferentiation perhaps foreshadowed WKH UHFHQWO\ XQFRYHUHG UROH RI MYC
LQ UHJXODWLQJ ´VWHPQHVVµ &RQGLWLRQDO NQRFNRXW PLFH KDYH GHPRQVWUDWHG an essential role for MYC in the normal GHYHORSPHQWDO FRQWURO RI KDHPDWR-SRLHWLFDQGQHXURQDOVWHPFHOOV
MYC KDV UHFHQWO\ EHHQ LGHQWLÀHG DV
RQH RI WKH IRXU JHQHV ZKRVH RYHUH[-pression could re-program normal ter- PLQDOO\GLIIHUHQWLDWHGÀEUREODVWVLQWRLQ-duced pluripotent stem (iPS) cells (66, 67). While it was later shown that MYC was dispensable for this process (68), it did underscore important implications for deregulated MYC in initiating and maintaining tumor stem cells. In fact the stem cell signature of undifferen-WLDWHG DQG DJJUHVVLYH WXPRXUV KDV great similarity to the phenotypes of 0<&DFWLYDWHGWXPRXUV
Genetic mechanisms of MYC targets deregulation
MYC transcription factor is considered one of the most potent oncoproteins in human cancer. The consequence of MYC dysregulation is the alteration of LPSRUWDQW ELRORJLFDO DFWLYLWLHV &DSD-ble of acting as both a transcriptional DFWLYDWRUDQGUHSUHVVRU0<&FRQWUROV WKHH[SUHVVLRQRIDYDVWDUUD\RIJHQHV together accounting for at least 10% of the human genome (69, 70). In gen-eral, genes targeted by MYC include mediators of metabolism, biosynthesis, '1$ UHSOLFDWLRQ DSRSWRVLV DQG FHOO cycle progression (71) such that ab-errant MYC expression is associated ZLWKXQFRQWUROOHGFHOOJURZWKGLYLVLRQ DQG PHWDVWDVLV ZKHUHDV ORVV RU inhibition of MYC expression reduces growth, promotes differentiation, and VHQVLWL]HV FHOOV WR '1$ GDPDJH ). Some of the most biologically import-ant targets are thought to be cyclins and cyclin-dependent kinases (CDKs),
resulting in accelerated cell cycling GRZQUHJXODWLRQ RI SKRVSKDWDVH and tensin homolog (PTEN) with con-sequent up-regulation of the phos-SKRLQRVLWLGHNLQDVHSURWHLQNLQDVH% PDPPDOLDQWDUJHWRIUDSDP\FLQ 3,. $.7P725 SDWKZD\ DQGVWDELOL]D-tion of the proapoptotic protein and WXPRU VXSSUHVVRU S ZKLFK FDQ E\SDVV WKH DSRSWRWLF %&/ SURJUDP (77). Consistent with its potent growth SURPRWLQJ SURSHUWLHV 0<& FDQ GULYH oncogenic transformation, and de-UHJXODWHG0<&H[SUHVVLRQDQGDFWLYLW\ is a hallmark of many human cancers. Indeed, by contrast to the highly reg-ulated state of MYC and the absence of N-MYC and L-MYC expression in nor-mal cells, cancer cells often harbour dysregulated expression of any one of these three MYC oncogenes.
The MYC transcriptional network also includes the direct regulation of a ODUJHQXPEHURIPLFUR51$V PL5V ZLWK oncogenic or tumor suppressor func-tion (78-80). MYC up-regulates the on- FRJHQLFPL5 FOXVWHUWKDWLVFRP-PRQO\DPSOLÀHGLQVHYHUDOVXEW\SHVRI DJJUHVVLYHO\PSKRPDV DQGLWV oncogenic function is mediated in part E\WKHGRZQUHJXODWLRQRI37(173 DQG()IDFLOLWDWLQJWKHDFWLYDWLRQRI WKH 3,.$.7 SDWKZD\ DQG WKH LQKLEL-WLRQ RI DSRSWRVLV 0<& UHSUHVVHV VHYHUDO PL5V ZLWK WXPRU VXSSUHVVRU IXQFWLRQE\WKHUHFUXLWPHQWRI+'$&V 7KHVH PL5V LQFOXGH PL5D PL5DPL5 DQGPL5ZKLFKUHJ-ulate crucial functions in neoplastic GHYHORSPHQW VXFK DV DSRSWRVLV PL-5D DQG PL5 WDUJHWLQJ %&/ DQG 73 UHVSHFWLYHO\ SUROLIHUDWLRQ PL5 D WDUJHWLQJ &'. RU FHOO GLI-IHUHQWLDWLRQ PL5D WDUJHWLQJ (=+ MYC itself is also
nega-WLYHO\ UHJXODWHG E\ VRPH PL5V VXFK DVPL5DQGPL5 PL5 LV LQ WXUQ UHSUHVVHG E\ (=+ FUHDWLQJ D SRVLWLYH DXWRUHJXODWRU\ ORRS 0<& PL5D(=+PL5 WKDW VXVWDLQV the persistent expression of MYC and (=+ SURPRWLQJ WKH PDOLJQDQW SKH-QRW\SHRIFHOOV 7KHLQWHUDFWLRQVRI the networks regulated by MYC and its target miRs are complex and suggest ÀQHWXQLQJ RI GLIIHUHQW SURFHVVHV WKDW may be targeted by new therapies *LYHQWKHHPHUJLQJSDWKRJH-QHWLFUROHRIPL51$VLQWKHPHWK\ODWLRQ status of cancer cells, this link between the regulatory function of MYC RYHU PL51$VLVSDUWLFXODUO\QRWHZRUWK\ 7KHWUDQVIRUPDWLYHFDSDFLW\RIMYC is often in concert with other oncogenes DQGYLUXVHVLQFOXGLQJWKHUDWVDUFRPD
(5$6) oncogene (88) and Epstein-Barr
YLUXV (%9 7KH FRUUHODWLRQ EH-WZHHQ (%9 DQG MYC is complex, be-FDXVH (%9DVVRFLDWHG SURWHLQV LQ WXUQ potentiate MYCDFWLYLW\
,QWULJXLQJO\WKHJHQHSURÀOHWUDQVFULS-WLRQDOO\ UHJXODWHG E\ 0<& YDULHV LQ GLIIHUHQWFHOOW\SHVZLWKUHODWLYHO\OLWWOH RYHUODS 7ZR UHFHQW VWXGLHV VKHG OLJKWRQWKLVSX]]OLQJREVHUYDWLRQVKRZ- LQJWKDWLQVWHDGRIDFWLYDWLQJDSDUWLF-ular gene signature, MYC acts as an DPSOLÀHURIWKHWUDQVFULEHGJHQHVLQD JLYHQFHOOE\XSORDGLQJWRWKHSURPRW-HUV RI DFWLYH JHQHV DQG HQKDQFLQJ WKHLU WUDQVFULSWLRQ 0<& GRHV not bind to promoters of silent genes DQGWKHUHIRUHDFWVDVDQDFWLYDWRURI the preexisting transcription program. 7KLVIXQFWLRQRI0<&PD\EHUHOHYDQW to understanding the increased ag-JUHVVLYHQHVVRIWXPRUVDVVRFLDWHGZLWK RWKHURQFRJHQLFHYHQWVFDUU\LQJMYC DOWHUDWLRQVDQGPD\RIIHUSHUVSHFWLYHV IRUQHZWKHUDSLHV
$OWKRXJK WKH WUDQVFULSWLRQDO UROH RI MYC has been well described, there are also non-transcriptional functions WKDW RQO\ UHFHQWO\ KDYH EHHQ DSSUH-FLDWHG LQFOXGLQJ UHJXODWLRQ RI P51$ translation and direct regulation of '1$UHSOLFDWLRQ)RULQVWDQFHMYC di-rectly promotes methyl cap formation RQ WKH · HQG RI SUHP51$ IRU PDQ\ genes, including cyclin D1 and CDK- DQG UHVXOWLQJ LQ HQKDQFHG P51$ WUDQVODWLRQ
ZZZ MECHANISMS OF MYC
DEREGULATION IN CANCER
Building on the awareness that, unlike other proto-oncogenes, MYC DFWLYD-tion was not a consequence of muta-tions in the coding sequence, research focused on identifying and under-standing other modes of oncogenic DFWLYDWLRQ 7KLV OHG WR WKH GLVFRYHU\ of three mechanisms through which MYC, and in turn other oncogenes, could be deregulated and promote transformation: insertional mutagen-esis, chromosomal translocation, and JHQH DPSOLÀFDWLRQ &RPELQHG WKHVH ÀQGLQJVOHGWKHZD\IRUWKHGLVFRYHU\ and understanding of oncogenes and SURYLGHG QHZ SDUDGLJPV IRU WKH JH-QHWLFEDVLVRIFDQFHUV Non-random chromosomal transloca-WLRQVKDGEHHQREVHUYHGLQDQXPEHU of malignancies, including Burkitt’s lym-phoma (BL) and Chronic Myeloid Leu-kemia. It was tempting to speculate that these translocations resulted in ab-errant expression of the same proto-on- FRJHQHVLGHQWLÀHGLQWKHDFXWHO\WUDQV-IRUPLQJ UHWURYLUXVHV 7KH PDSSLQJ RI MYC to the long arm of chromosome 8 JDYHFUHGHQFHWRWKLVK\SRWKHVLV 6SHFLÀFDOO\ %XUNLWW·V O\PSKRPDV
had been characterized to contain re-ciprocal translocations between chro-PRVRPHDQGFKURPRVRPHVRU ZKLFKKDUERXULPPXQRJOREXOLQ ,J KHDY\ DQG OLJKW FKDLQ JHQHV ,W ZDVWKHQGLVFRYHUHGWKDWWKHFDQFHULV GULYHQE\DFWLYDWHGH[SUHVVLRQRIMYC resulting from the translocation. One of WKHÀUVW0<&WUDQVJHQLFPLFH(Ǎ0<& ZDVGHYHORSHGWRPRGHO%XUNLWW·VO\P-SKRPD$FWLYDWHGMYC expression was GULYHQIURPWKHKHDY\FKDLQHQKDQFHU (Ǎ OHDGLQJ WR FORQDO %FHOO O\PSKR-mas. Mouse plasmacytomas were sim-ilarly found to be a consequence of
MYC WUDQVORFDWLRQ ZLWK WKH ,J KHDY\
chain locus (108, 109).
It was well established that cancer cells contained a number of chromo-somal abnormalities and contributions of these aberrations to cellular trans-formation were largely appreciated WKURXJKWKHVWXG\RI0<& $PSOLÀFDWLRQ RI MYC and/or dysreg-XODWHG H[SUHVVLRQ LV HYLGHQW LQ PDQ\ tumors including melanomas and car-cinomas of the breast, prostate and colon. The deregulation of MYC plays D GHFLVLYH UROH LQ O\PSKRPDJHQHVLV E\ GULYLQJ WKH FHOOV WKURXJK WKH FHOO cycle. In fact, as a result of the trans-location, the normal control mecha-nisms of MYC expression are disrupt-HG OHDGLQJ WR FRQVWLWXWLYH H[SUHVVLRQ of the protein throughout the cell cy-FOH %ULHÁ\ 0<& SURWHLQ LV QRW RQO\ D potent inducer of proliferation, it also induces as a fail-safe mechanism, a large number of pro-apoptotic and inhibits expression of anti-apoptotic genes, thereby inducing apoptosis or SUHGLVSRVLQJ FHOOV WR DSRSWRVLV $V D consequence, MYCGULYHQWXPRUVXVX-DOO\KDYHDFTXLUHGDGGLWLRQDOJHQHWLF PXWDWLRQVRUHSLJHQHWLFPRGLÀFDWLRQV
WKDWSURPRWHFHOOVXUYLYDODQGVKLIWWKH balance between proliferation and apoptosis towards proliferation. Impor-WDQWO\DPDMRUGHYHORSPHQWZLWKLQWKH past decade has been the realization that MYC dysregulation is not restricted to gross genetic changes at the MYC locus, such as chromosomal transloca-tion, insertional mutagenesis and gene DPSOLÀFDWLRQEXWMYC can be dereg-XODWHGE\RQHRIVHYHUDOPHFKDQLVPV WKDWWDUJHWLWVH[SUHVVLRQDQGRUDFWLYL-ty either directly or indirectly.
Deregulation of MYC in human lymphomas
The constellation of MYC effects on JHQHVLQYROYHGLQSUROLIHUDWLRQKDVOHG
to the concept of MYCGULYHQ O\P-SKRPDV 7KHFODVVLFMYCGULYHQ lymphoma is BL, in which balanced re-arrangements between chromosome DQG HLWKHU FKURPRVRPH LPPX-QRJOREXOLQ ,J KHDY\ FKDLQ FKUR-PRVRPH ,J*ODPEGDOLJKWFKDLQ RU FKURPRVRPH ,J* NDSSD OLJKW FKDLQ OHDG WR D KLJKO\ SUROLIHUDWLYH lymphoid malignancy with a propensi- W\IRUH[WUDQRGDOLQYROYHPHQWSDUWLFX-larly in immunocompromised patients. $FFRUGLQJ WR WKH ODVW :+2 FODVVLÀFD-tion, other lymphomas commonly as-sociated with MYC deregulation are diffuse large B-cell lymphoma (DLBCL), %FHOO O\PSKRPD XQFODVVLÀDEOH ZLWK features intermediate between
DLB-TABLE 1 Lymphoid neoplasms characterized by MYC deregulation. Clinic Morphology Immunohisto-
chemistry Molecular Biology Burkitt lymphoma (BL) Extranodal sites of children and young adults. YDULDQWV endemic, VSRUDGLF+,9 associated &RKHVLYH medium-sized cells with coarse chromatin, in a starry sky pattern
The neoplastic cells H[SUHVV&'&' &'&' D&' %&/EXWDUHQHJDWLYH IRU%&/SUROLIHUDWLYH LQGH[ .L ! W RUYDULDQW W RUW >90% Diffuse large B-cell lymphoma (DLBCL) $GXOWDQG elderly with enlarging mass in nodal and extranodal sites Diffuse growth pattern with centroblastic, immunoblastic, anaplastic or mixed morphology
Pan-B cell antigens SRVLWLYHZLWK expression of germinal center markers in a subset of cases; SUROLIHUDWLYHLQGH[ .L W translocation LQYROYLQJT two groups LGHQWLÀHGE\ gene expression SURÀOHWKH$%& DQG*&W\SH B cell lymphoma, XQFODVVLÀDEOH Older patients presenting with nodal and extranodal disease, usually in an DGYDQFHG clinical stage Diffuse growth pattern with intermediate-sized cells, some admixed larger cells, irregular nuclei with single prominent nucleoli Expression of CD19, &'&'&' D &'%&/YDULDEO\ BCL6 W DQG RWKHUW TT complex karyotype, MYC rearrangement WR,*DQGQRQ ,*SDUWQHURIWHQ accompanied by %&/ or %&/ rearrangement >>> Segue
&/ DQG %/ %&/8 3ODVPDEODVWLF O\P-phoma (PBL), Plasmacytoma (PC) and $QDSODVWLF O\PSKRPDV .LQDVHSRVL-WLYH /DUJH %FHOO /\PSKRPD 7DEOH and )LJXUH summarize the clinical, morphological, immunophenotypical and molecular biology features of the lymphoid neoplasms characterized by
MYC
GHUHJXODWLRQ$SDUWIURPWKHW\S- LFDOFKDUDFWHULVWLFVRIWKHDERYHPHQ-tioned lymphomas, genetic abnor-PDOLWLHVLQYROYLQJMYC results in a more DJJUHVVLYHSKHQRW\SHRIWXPRXUVFHOOV
and a poor prognosis, largely indepen-dent of other clinical and molecular ULVNIDFWRUV
Novel concept in MYC-related B-cell lymphomas
MYC aberrations can be detected by VWDQGDUG F\WRJHQHWLFV LQWHUSKDVH ÁX-orescence in situ K\EULGL]DWLRQ ),6+ FRPSDUDWLYH JHQRPLF K\EULGL]DWLRQ and most recently immunohistochem-LVWU\ ,+& ,Q UHFHQW \HDUV LW has been well established that patients >>> Seguito
Clinic Morphology Immunohisto- chemistry Molecular Biology Plasmacytoma Middle-aged patients, bone pain at site of LQYROYHPHQWRU pathological fracture. Soft tissue extension may produce a palpable mass Poorly differentiated plasma cells (plasmablastic or anaplastic) with eccentric nuclei, and dispersed chromatin Neoplastic plasma cells H[SUHVV&' $ &'&' and monotypic cytoplasmatic immunoglobulins (Ig), they lack surface Ig Immunoglobulin KHDY\DQGOLJKW chain genes rearrangement Plasmablastic lymphoma $JJUHVVLYH neoplasm usually present in extranodal sites and frequently in the head and neck region in patients with different LPPXQRGHÀFLHQF\ states Diffuse proliferation of large B cells with immunoblastic morphology, admix with small to intermediate-sized cells Neoplastic cells H[SUHVV&' &'080 and they are QHJDWLYHIRU &'3$; SUROLIHUDWLYH index (Ki-67): >90%. MYC translocations are encountered in RIFDVHV usually with Igh loci, EBER SRVLWLYHLQ 70% of cases. ALK-positive DLBCL Young patients RFFXULQWKH pediatric age group) commonly with nodal disease
The tumor FHOOVKDYHDQ immunoblastic or plasmablastic appearance, sinusoidal LQÀOWUDWLRQLV common Neoplastic cells lack mature B-cell markers but express (0$NDSSDRU lambda light chain, (most RIWHQ,J$ &'$/. 8SUHJXODWLRQRI the $/. gene is mainly due to the presence RIW S T &/7& (clathrin)/$/.. Rare cases with W S T (130$/.) translocation KDYHDOVREHHQ reported
),*85( Lymphoid neoplasms characterized by MYCGHUHJXODWLRQ $ %XUNLWWO\PSKRPD%/ % GLIIXVHODUJH%FHOOO\PSKRPD'/%&/ & %FHOOO\PSKRPDXQFODVVLÀDEOHZLWKIHDWXUHVLQWHU-mediate between DLBCL and BL; D: plasmablastic lymphoma; haematoxylin and eosin, origi-QDOPDJQLÀFDWLRQ20 [
KDUERXULQJ ),6+GHWHFWHG JHQHDFWL-YDWLQJEUHDNVLQERWKMYC and %&/, suffer from poor response to standard WKHUDS\ DQG KDYH DQ DGYHUVH SURJ-QRVLV &RQYHQWLRQDOF\WRJHQHWLFV or molecular biology method could be considered the gold standard for the LGHQWLÀFDWLRQ RI MYC rearrangements, because they identify the translocation SDWWHUQV)URPDWHFKQLFDOVWDQGSRLQW to test for the MYC rearrangement, break-apart probes and not dual-fusion are typically used to account for the
non-,*+ translocation partners of MYC.
)RU%&/ either break-apart or ,*+%&/ dual fusion testing strategy could be
used, whereas for %&/ translocations
break-apart probes are recommended &\WRJHQHWLF DQDO\VLV KRZHYHU is cumbersome, time-consuming and not routinely performed in the work-up of lymphomas at many centers. More-RYHU ),6+ WHFKQRORJ\ LV JHQHUDOO\ QRW designed to detect genetic deregu-lation that affects gene expression on the transcriptional and translational OHYHOV 7KH DYDLODELOLW\ RI DQWL0<& DQ-WLERG\ FORQH$EGLOXWLRQ $EFDP&DPEULGJH 8QLWHG .LQJGRP DPHQDEOH IRU XVH LQ IRUPDOLQÀ[HG SDUDIÀQHPEHGGHG WLVVXH RIIHUV D OHVV costly and less laborious means of
de-WHFWLQJ 0<& RYHUH[SUHVVLRQ DQG UHS-resents a key step forward in studying 0<&DVVRFLDWHGO\PSKRPDV %\ FRPSDULQJ H[SUHVVLRQ SURÀOHV RI MYC gene rearrangement and MYC protein expression emerged that MYC gene rearrangements do not neces-sarily correlate with MYC protein ex-pression. In fact by applying immuno-histochemistry, the frequency of MYC protein expression appears much KLJKHU WKDQ ZKDW LV GHWHFWHG E\ ),6+ standard method (116). Therefore, nowadays the key problem in the he-PDWRSDWKRORJ\ ÀHOG LV WR GHÀQH WKH clinical impact of the double/triple ex-pressor status apart from the presence of genetic alterations characterizing the so-called double/triple hit (DH/TH) O\PSKRPDV $OWKRXJK JHQRW\SH FRQ-trols phenotype because genes direct the products of proteins, there are pro-WHLQVLQWXUQWKDWGLFWDWHYLUWXDOO\HYHU\ reactions in the cells and thus are di- UHFWO\UHVSRQVLEOHIRUREVHUYDEOHFKDU- DFWHULVWLFVDQGHIIHFWV)URPDELRORJ-LFDO SRLQW RI YLHZ SKHQRW\SH DV WKH results of multiple cross-talks between JHQHV SURWHLQV DQG HQYLURQPHQW LV PRUHUHOHYDQWWKDQJHQRW\SHSURWHLQV H[SUHVVLRQ OHYHOV OLNHO\ UHSUHVHQWLQJ D PRUHGLUHFWPHDVXUHRIWKHDFWLYLW\RI DSDUWLFXODUJHQH$FFRUGLQJO\DVVHVV-LQJWKHH[SUHVVLRQRI0<&%&/DQG %&/E\,+&LVDWWUDFWLYHEHFDXVHWKLV should identify double/triple-express-ing lymphoma patients whose disease DUHGULYHQE\LQFUHDVHG0<&DQGRU %&/ DQGRU %&/ DFWLYLW\ VHFRQG-DU\ WR D YDULHW\ RI PHFKDQLVPV QRW VROHO\WUDQVORFDWLRQV
+RZHYHU WKHUH LV D VLJQLÀFDWLYH LQWHU-SUHWDWLYHFKDOOHQJHWRGHÀQHWKHVFRUH RI SRVLWLYLW\ IRU 0<& %&/ %&/ DO-
WKRXJK$XWKRUVKDYHXVHGWKHWKUHVK-ROGRIJUHDWHUWKDQIRU0<&DQG JUHDWHU WKDQ IRU %&/ UHVSHF-WLYHO\0RUHRYHU0<&VWDLQLQJPD\EH heterogeneous, rendering accurate TXDQWLÀFDWLRQZRQGHULQJ,QDGGLWLRQ many double-expressor lymphomas UHÁHFW '/%&/ IRU LQVWDQFH DFWLYDWHG %FHOO $%& W\SHRI'/%&/LQZKLFKWKH 0<&DQG%&/DUHRYHUH[SUHVVHGE\ other mechanisms than translocations
)RUDOOWKHVHUHDVRQVWKHXSGDWHG:+2 FODVVLÀFDWLRQRIWXPRXUVRIKHPDWRSRL-etic and lymphoid tissues that will be published in the next future, suggests WROLPLWWKHGHÀQLWLRQRI'+7+O\PSKR-PDRQO\LQWKHFDVHLQZKLFKWKH´KLWµ could be demonstrated by cytogenet-LFRUPROHFXODUELRORJ\$FFRUGLQJO\LW SURSRVHVDQRYHOFODVVLÀFDWLRQIRUKLJK grade B-cell lymphomas, including: diffuse large B-cell lymphoma, not oth- HUZLVHVSHFLÀHG KLJKJUDGH%FHOOO\P-SKRPDVQRWRWKHUZLVHVSHFLÀHG KLJK
grade B-cell lymphomas with %&/
and/or %&/ and MYC
rearrange-ments. 7DEOH summarizes the clinical,
morphological,
immunophenotypi-cal and molecular biology features of WKHVHQRYHOVXEW\SHV
ZZZ MYC-TARGETED THERAPY
Because of its oncogenic properties in neoplastic cells, MYC has become an interesting and feasible target for QRYHOWKHUDSLHVRIDYDULHW\RIKXPDQ PDOLJQDQFLHV +RZHYHU 0<& SURWHLQ itself has generally been considered ´XQGUXJJDEOHµDQGWKHSRWHQWLDODS-SURDFKHV KDYH EHHQ GLUHFWHG DW UH-GXFLQJLWVH[SUHVVLRQ ,WKDVEHHQ VKRZQ WKDW VHYHUDO VPDOO PROHFXOHV target the transcription of MYC gene directly or the MYC downstream
path-ZD\V(VSHFLDOO\*ULFKUHJLRQRIMYC promoter has become a promising tar-get. Many reports demonstrate that
low-molecular weight compounds
KDYH D SRWHQWLDO WR EH GHYHORSHG LQWRWKHUDSHXWLFGUXJVLQLQGLYLGXDOL]HG FDQFHU WKHUDS\ (YHQ ZLWK WKH DG-YDQFHVLQWKHÀHOGRIGUXJGHVLJQDQG
TABLE 2 1RYHOVXEW\SHVRIKLJKJUDGH%FHOOO\PSKRPDVLQFOXGHGLQWKHXSGDWHG:+2FODV-sification of tumours of hematopoietic and lymphoid tissues.
Clinic Morphology
Immunohisto-chemistry Molecular Biology DLBCL, not otherwise VSHFLÀHG 126 $GXOWDQG elderly, nodal and extranodal sites
Large tumour cells with abundant cytoplasm, large nuclei and prominent nucleoli Pan-B cell antigens SRVLWLYLW\ .L $%&RU*&W\SH
High grade B-cell
O\PSKRPD126 Elderly patients
Histologic appearance that resembles Burkitt lymphoma more than DLBCL; irregular nuclear contour; although many areas mimic DLBCL, the nuclear size remains small 3RVLWLYLW\ IRU&' QHJDWLYLW\IRU 7G7080 ,5) BCL6, CD10,Ki-67 YDULDEOH 0<& expression depends on the presence of MYC translocation $SSUR[LPDWHO\ RIWKH FDVHVKDYHDMYC breakpoint (with or without increased copy numbers or UDUHO\DPSOLÀFDWLRQ RITLQYROYLQJ %&/). The presence of %&/ and/or %&/ breakpoint in combination with MYC breakpoint should be excluded High grade B-cell
lymphoma, with BCL2 and/or BCL6 and MYC rearrangements/ translocations Elderly patients, two peaks of incidence DQG years). Widespread disease, including LQYROYHPHQW of lymph nodes with more than one extranodal site, bone PDUURZ DQG &16 60%) )LEURVLVDVZHOO as starry sky macrophages may be (focally) present. The number of PLWRWLFÀJXUHV and apoptotic ÀJXUHVLVKLJKO\ YDULDEOH 7KHQXFOHLKDYH DYDULDEOHVL]H and contour. The cytoplasm is usually more abundant and less basophilic than in BL Neoplastic cells are &' &' &' D3$; %&/SRVLWLYH and TdT QHJDWLYH CD10 and %&/ 080,5) In addition to the MYC rearrangement, all cases contain %&/ rearrangement at TDQGRUD%&/ rearrangement at T +*%/'+RIWHQ KDYHFRPSOH[ karyotypes with many other structural and numerical abnormalities Sequencing studies UHYHDOIUHTXHQWTP53 mutations mainly in the 0<& %&/ double hit cases, few 0<' mutations
+,9 +XPDQ,PPXQRGHILFLHQF\9LUXV$%& $FWLYDWHG%FHOOV*& JHUPLQDOFHQWHU(%(5 (SVWHLQ%DUUHQ-FRGLQJUHJLRQ$/. $QDSODVWLFO\PSKRPDNLQDVH&16 FHQWUDOQHUYRXVV\VWHP
in the mechanisms underlying the MYC RYHUH[SUHVVLRQ LQ WXPRU FHOOV LW LV VWLOO GLIÀFXOW WR REWDLQ KLJKO\ VSHFLÀF DQG DFWLYHDQWLFDQFHUGUXJV
6HYHUDO DSSURDFKHV PD\ EH HP-SOR\HGWRWDUJHW0<&DFWLYLWLHV
– %ORFNLQJ 0<& DFWLYDWLRQ one small PROHFXOH ) UHFRJQL]HV WKH 0<& DPLQR DFLG UHVLGXHV which reside within the HLH-LZ domain LQKLELWLQJ WKH 0<&0$; KHWHURGL-PHUL]DWLRQ 'HVSLWHLWVVXFFHVVin vitro (cell cycle arrest and apoptosis) )GLGQRWSURYHWREHHIIHFWLYH in in vivo animal studies primarily be-cause of its limiting PK/PD properties. – ,QKLELWLQJ0<&DVVRFLDWHGFKURPDWLQ PRGLÀFDWLRQV a small molecule, named -4ZDVGHVLJQHGWR%5'WKHÀUVWEUR-modomain of the BET family member %5'7KHPROHFXOHLQKLELWV0<&SDWK-ZD\DFWLYDWLRQE\WDUJHWLQJFKURPDWLQ PRGLÀFDWLRQVDVVRFLDWHGZLWKWKHSUR-cess of MYC-mediated transcriptional DFWLYDWLRQ 7KDQNV WR HQFRXUDJLQJ UH-sults in in vitro models, further preclini-FDO HIÀFDF\ VWXGLHV RQ %5' LQKLELWLRQ against a wider range of cancers with HOHYDWHG 0<& H[SUHVVLRQ via different mechanisms are ongoing.
– ([SORLWLQJ0<&GHSHQGHQWV\QWKHWLF OHWKDOLQWHUDFWLRQV the essential role of MYC in both cancer and normal tissue GHYHORSPHQW DQG KRPHRVWDVLV UDLVHV WKH FRQFHUQ WKDW HYHQ LI GLUHFW 0<& LQKLELWRUV FRXOG EH GHYHORSHG WKH\ PLJKWEHWRRWR[LFIRUFOLQLFDOXVH$Q DOWHUQDWLYHDSSURDFKLVWRLGHQWLI\DQG WDUJHW VLJQDOOLQJ SDWKZD\V DFWLYDWHG E\ 0<& VHOHFWLYHO\ LQ WXPRU FHOOV EXW QRW LQ QRQWXPRULJHQLF FHOOV 6HYHUDO 3RO\ $'3ULERVH SRO\PHUDVH 3$53 LQKLELWRUV DUH FXUUHQWO\ EHLQJ HYDOX-DWHGLQODWHSKDVHFOLQLFDOWULDOV3$53 LQKLELWRUV WKXV VHUYH DV DQ LPSRUWDQW
proof of concept that synthetic lethal DSSURDFKHVDUHFOLQLFDOO\UHOHYDQWDQG exploitable.
– 7DUJHWLQJFHOOF\FOHNLQDVHV cancer
FHOOV ZLWK HOHYDWHG 0<& H[SUHVVLRQ RIWHQ H[KLELW KLJKO\ SUROLIHUDWLYH DQG poorly differentiated phenotypes, sug-JHVWLQJ WKDW WKH 0<&DFWLYDWHG FHOOV DUH SRLVHG WR FRQWLQXRXVO\ GULYH WKH cell cycle. It may also suggest that oth- HUFHOOXODUSURFHVVHVKDYHKDGWRDG-MXVWWRDFFRPPRGDWHVXFKVLJQLÀFDQW FKDQJHV LQ FHOO SK\VLRORJ\ %DVHGRQWKHVHREVHUYDWLRQVDGLQDF-iclib phase I trial using MYC expression and signalling as a clinical correlate biomarker of response has been ini-WLDWHG &OLQLFDO7ULDOVJRY ,GHQWLÀHU 1&7 7KLV LV DPRQJ WKH ÀUVW trials in which a small molecule CDK inhibitor is used to determine whether 0<& RYHUH[SUHVVLQJ FDQFHUV DUH VH-OHFWLYHO\WDUJHWHG$PRQJRWKHU&'.V DQLQWHUSKDVHFHOOF\FOHNLQDVH&'. was reported to be essential for the YLDELOLW\ RI QHXUREODVWRPD FHOOV ZLWK
MYCN DPSOLÀFDWLRQ
&'.VSH-FLÀF VL51$V DQG VHOLFLFOLE DOVR NQRZQ DVURVFRYLWLQH DVPDOOPROHFXOH&'. LQKLELWRUZLWKKLJKHUVSHFLÀFLW\WRZDUG &'.DQG LQGXFHGDSRSWRVLVLQ a panel of established neuroblastoma FHOOOLQHV7KHVHQVLWLYLW\WR&'.LQKLEL-WLRQZDVGHSHQGHQWRQZLOGW\SHS DQG 0<&1 RYHUH[SUHVVLRQ 6HOLFLFOLE ZDV SUHYLRXVO\ HYDOXDWHG LQ SKDVH , and II trials. The potential clinical ef-ÀFDF\ RI &'. LQKLELWLRQ KDV EHHQ FRQWURYHUVLDO (DUOLHU JHQHWLFV VWXGLHV GHPRQVWUDWHG WKDW &'. ZDV QRW HV-sential for mammalian embryonic de-YHORSPHQWin vivo or for the cell cycle progression of non tumorigenic as well
as tumorigenic cells in vitro
specif-LF VPDOO PROHFXOH LQKLELWLRQ RI &'. NLQDVH DFWLYLW\ GLPLQLVKHG FHOO F\FOH progression in non-transformed and MYC-transformed epithelial cells with-RXWLQGXFWLRQRIFHOOGHDWK ,QWHUHVWLQJO\ &'. JHQHWLF GHSOHWLRQ
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in accelerated cell proliferation, which was accompanied by the upregula-tion of CDK1 that has been shown to be capable of functionally compen-sating for any of the interphase CDKs :KHWKHU &'. LQKLELWRUV ZLOO KDYH D UROH IRU WKHUDS\ RI QHXUREODV-WRPDV RU RWKHU 0<& RU 0<&1GULYHQ tumors remains to be determined. Mi-WRVLV UHJXODWRUV $XURUD NLQDVHV $ DQG B, which control mitotic spindle at-WDFKPHQW DQG G\QDPLFV KDYH EHHQ targeted in MYC-deregulated cancer FHOOV,WZDVUHSRUWHGWKDWPXOWLSOH$X-URUDVHOHFWLYHVPDOOPROHFXOHLQKLELWRUV caused strong antitumorigenic ef-fects-including cell cycle arrest, apop-tosis, and autophagy-in model epithe-lial cells in a MYC-dependent manner 6PDOO PROHFXOH $XURUD NLQDVH LQKLELWRUVZHUHDOVRHIIHFWLYHLQH[WHQG-LQJ DQLPDO VXUYLYDO LQ PXOWLSOH PRXVH models of MYC-induced lymphomas 0RUHUHFHQWO\DQ$XURUDNLQDVH small molecule inhibitor, alisertib, was IRXQGWRLQFUHDVHDQLPDOVXUYLYDOLQD mouse model of MYCNGULYHQ QHX-UREODVWRPD LQ ZKLFK $XURUD NLQDVH plays a key role in maintaining MYCN protein stability that is central to its tu- PRULJHQLFDFWLYLW\ $OLVHUWLELVFXU-UHQWO\ EHLQJ HYDOXDWHG LQ QXPHURXV phase I and II trials. Chk1-an essential NLQDVH LQYROYHG LQ '1$ GDPDJH DQG FHOOXODU VWUHVVUHVSRQVLYH SDWKZD\VLV another cell cycle-related kinase that has been targeted in MYC-deregulat-ed cancer cells. The hypothesis is that
KLJKO\SUROLIHUDWLYH0<&GULYHQFDQFHU FHOOVLQFUHDVHHQGRJHQRXV'1$GDP- DJHIURPUHSOLFDWLYHVWUHVV'1$UHSOL-FDWLRQIRUNFROODSVHRUR[LGDWLYHVWUHVV $&KNFKHFNSRLQWDOORZVIRUUHSDLURI these insults and protects rapidly prolif- HUDWLQJ0<&GULYHQFHOOVIURPWKHVHHQ-GRJHQRXV'1$GDPDJHLQVXOWV – 2WKHU SRVVLEOH WDUJHW beyond the cell cycle, MYC has also been shown to regulate numerous additional sig-nalling pathways critical for tumor GHYHORSPHQW DQG PDLQWHQDQFH $ current challenge is to identify addi-tional synthetic lethal targets in these signalling pathways downstream of 0<& $PRQJ DOO WKH SRVVLEOH WDUJHWV there are: small ubiquitin-related mod-LÀHU 6802 DFWLYDWLQJ HQ]\PH 6$( D KHWHURGLPHU FRPSOH[ PHWDEROLVP UHJXODWRU HQ]\PHV · $03DFWLYDWHGNLQDVH $03. UHODWHG NLQDVH $5. RU$03.LWVHOI ZZZ $/22.)25:$5' 7RRYHUFRPHWKHFRQÁLFWLQJGDWDSUHV-ent in the literature on the correlation among MYC gene aberrations and 0<&SURWHLQH[SUHVVLRQZHUHYLHZHG a total of 119 clinical, morphological and immunophenotypical typical BL cases and we checked the expression RI0<&DWERWKP51$DQGSURWHLQOHY- HOE\UHVSHFWLYHO\573&5DQGLPPXQR- KLVWRFKHPLVWU\,QDGGLWLRQ),6+DQDO\-sis for MYC-translocation was also per-IRUPHGE\XVLQJWKHDYDLODEOHSUREHV (dual-color break-apart probe). Dif-ferent patterns of MYC gene translo-cation/MYC protein expression were LGHQWLÀHG
– 99 cases bearing a translocation in-YROYLQJMYC gene expressed MYC at ERWKP51$DQGSURWHLQOHYHO SRVLWLYLW\
in almost 80% of neoplastic cells). This ÀQGLQJLVLQOLQHZLWKWKHGDWDUHSRUWHG LQWKHOLWHUDWXUH
– 10 cases in which a translocation LQYROYLQJ MYC gene was not detect-DEOH H[SUHVVHG 0<& DW ERWK P51$ DQGSURWHLQOHYHO,WLVNQRZQWKDWQRQH of the techniques currently used to di-agnose genetic changes can unam-biguously rule out all of MYC translo-FDWLRQV ,QIDFWWKLVPD\EHGXH WR WHFKQLFDO IDLOXUH RI ),6+ DV WKHVH FDVHV PD\ SUHVHQW ZLWK D YHU\ VPDOO excision of MYC and insertion of the
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– 10 cases showed MYC gene translo-cation but did not express MYC at pro-WHLQOHYHO7RHYDOXDWHLIWKHQHJDWLYLW\ for MYC protein was due to a defect in the transcription of MYC gene or in the assembling of the protein, RT-PCR for 0<&P51$ZDVSHUIRUPHG:HIRXQG that among the 10 cases not express-LQJ 0<& SURWHLQ ODFNHG DOVR 0<& P51$$VWXG\LVRQJRLQJLQRXUODER-ratory to shed new light on how a MYC gene aberration does not result in MYC P51$DQGSURWHLQRYHUH[SUHVVLRQ
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homology to myc cellular oncogene is shared by human neuroblastoma cell lines and a neuroblastoma tumour. Na-WXUH
.RKO1(7UDQVSRVLWLRQDQGDPSOLÀFDWLRQRI oncogene-related sequences in human QHXUREODVWRPDV&HOO 9. Schwab M. Enhanced expression of
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Oscar-wor-thy role of Myc in apoptosis. Semin Can-FHU%LRO
6WUDVVHU$+DUULV$:%DWK0/HWDO1RY-HO SULPLWLYH O\PSKRLG WXPRXUV LQGXFHG in transgenic mice by cooperation be-WZHHQP\FDQGEFO1DWXUH
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=LQG\ ) (LVFKHQ &0 5DQGOH '+ HW DO 0\FVLJQDOLQJYLDWKH$5)WXPRUVXSSUHV-VRU UHJXODWHV SGHSHQGHQW DSRSWRVLV DQG LPPRUWDOL]DWLRQ *HQHV 'HY )LQFK$3UHVFRWW-6KFKRUV.HWDO%FO[/ JDLQRIIXQFWLRQDQGS $5)ORVVRIIXQF-tion cooperate oncogenically with Myc LQ YLYR E\ GLVWLQFW PHFKDQLVPV &DQFHU &HOO
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-DFREV -- 6FKHLMHQ % 9RQFNHQ -: HW al. Bmi-1 collaborates with c-Myc in tu-morigenesis by inhibiting c-Myc-induced DSRSWRVLV YLD ,1.D$5) *HQHV 'HY
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VXSSUHVVLRQRI%FO;/RU%FOLVE\SDVVHG during lymphomagenesis. Mol Cell Biol.
0DFOHDQ.+.HOOHU8%5RGULJXH]*DOLQ-do C, et al. c-Myc augments (gamma) irradiation-induced apoptosis by sup-SUHVVLQJ %FO;/ 0RO &HOO %LRO
'DQVHQ 7% :KLWÀHOG - 5RVWNHU ) HW DO 6SHFLÀFUHTXLUHPHQWIRU%D[QRW%DNLQ Myc-induced apoptosis and tumor sup-pression in vivo.-%LRO&KHP
-XLQ3+XQW$/LWWOHZRRG7HWDOF0\F functionally cooperates with Bax to in-GXFH DSRSWRVLV 0RO &HOO %LRO
$QQLV 0* 6RXFLH (/ 'OXJRV] 3- HW DO Bax forms multispanning monomers that oligomerize to permeabilize membranes during apoptosis. EMBO J.
6RXFLH(/$QQLV0*6HGLY\-HWDO0\F potentiates apoptosis by stimulating Bax DFWLYLW\ DW WKH PLWRFKRQGULD 0RO &HOO %LRO
0XUUH&0F&DZ36%DOWLPRUH'$QHZ '1$ ELQGLQJ DQG GLPHUL]DWLRQ PRWLI in immunoglobulin enhancer binding, daughterless, MyoD, and myc proteins. &HOO
/DQGVFKXO] :+ -RKQVRQ 3) 0F.QLJKW SL. The leucine zipper: a hypothetical VWUXFWXUHFRPPRQWRDQHZFODVVRI'1$ ELQGLQJ SURWHLQV 6FLHQFH %ODFNZHOO 7..UHW]QHU/%ODFNZRRG(0 HWDO6HTXHQFHVSHFLÀF'1$ELQGLQJE\ WKH F0\F SURWHLQ 6FLHQFH 3UHQGHUJDVW*&=LII(%0HWK\ODWLRQVHQ-VLWLYHVHTXHQFHVSHFLÀF'1$ELQGLQJE\ the c-Myc basic region. Science. 1991;
%ODFNZRRG(0(LVHQPDQ510D[ DKH-lix-loop-helix zipper protein that forms a VHTXHQFHVSHFLÀF'1$ELQGLQJFRPSOH[ ZLWK0\F6FLHQFH $\HU'(.UHW]QHU/(LVHQPDQ510DG
a heterodimeric partner for Max that DQWDJRQL]HV0\FWUDQVFULSWLRQDODFWLYLW\ &HOO
5RWWPDQQ6/XVFKHU%7KH0DGVLGHRI the Max network: antagonizing the func-tion of Myc and more. Curr Top Microbiol ,PPXQRO
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,ULWDQL%0(LVHQPDQ51F0\FHQKDQF-es protein synth,ULWDQL%0(LVHQPDQ51F0\FHQKDQF-esis and cell size during % O\PSKRF\WH GHYHORSPHQW 3URF 1DWO $FDG6FL86$
'DQJ &9 /H $ *DR 3 0<&LQGXFHG cancer cell energy metabolism and therapeutic opportunities. Clin Cancer 5HV
YDQ5LJJHOHQ-<HWLO$)HOVKHU':0<&DVD regulator of ribosome biogenesis and protein V\QWKHVLV1DW5HY&DQFHU 0DL6)OXUL06LZDUVNL'HWDO*HQRPLFLQ-VWDELOLW\LQ0\F(5DFWLYDWHG5DW$0\F(5 FHOOV&KURPRVRPH5HV /L 4 'DQJ &9 F0\F RYHUH[SUHVVLRQ XQFRXSOHV'1$UHSOLFDWLRQIURPPLWRVLV 0RO&HOO%LRO )HOVKHU ': %LVKRS -0 7UDQVLHQW H[FHVV RI0<&DFWLYLW\FDQHOLFLWJHQRPLFLQVWD-ELOLW\DQGWXPRULJHQHVLV3URF1DWO$FDG 6FL86$ <LQ;<*URYH/'DWWD16HWDO&P\F RYHUH[SUHVVLRQ DQG S ORVV FRRSHUDWH to promote genomic instability. Onco-JHQH
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3URFKRZQLN(9/L<7KHHYHUH[SDQGLQJ role for c-Myc in promoting genomic in-VWDELOLW\&HOO&\FOH 1JR&9*HH0$NKWDU1HWDO$QLQYLYR
function for the transforming Myc protein: elicitation of the angiogenic phenotype. &HOO*URZWK'LIIHU
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DO5DVPRGXODWHV0\FDFWLYLW\WRUHSUHVV thrombospond1 expression and in-crease tumor angiogenesis. Cancer Cell.
3HOHQJDULV6.KDQ0(YDQ*,6XSSUHV-sion of Myc-induced apoptosis in (beta)
cells exposes multiple oncogenic prop-erties of Myc and triggers carcinogenic SURJUHVVLRQ&HOO
'DQJ&95HWKLQNLQJWKH:DUEXUJHIIHFW with Myc micromanaging glutamine me-WDEROLVP&DQFHU5HV 'H%HUDUGLQLV 5- /XP -- +DW]LYDVVLOLRX
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:LVH '5 'H%HUDUGLQLV 5- 0DQFXVR $6 et al. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine DGGLFWLRQ3URF1DWO$FDG6FL86$
'UD\WRQ65RZH--RQHV5HWDO7XPRU VXSSUHVVRUS,1.DGHWHUPLQHVVHQVLWLY-ity of human cells to transformation by cooperating cellular oncogenes. Can-FHU&HOO
60. Campaner S, Doni M, Hydbring P, et al. &GNVXSSUHVVHVFHOOXODUVHQHVFHQFHLQ-duced by the c-myc oncogene. Nat Cell %LRO
+\GEULQJ3/DUVVRQ/*&GN DNH\UHJX-lator of the senescence control function of 0\F$JLQJ $OEDQ\1< YDQ5LJJHOHQ-)HOVKHU':0\FDQGD
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:LOVRQ$0XUSK\0-2VNDUVVRQ7HWDO c-Myc controls the balance between hematopoietic stem cell self-renewal DQGGLIIHUHQWLDWLRQ*HQHV'HY
.QRHSÁHU 36 &KHQJ 3) (LVHQPDQ 51 N-myc is essential during neurogenesis for the rapid expansion of progenitor cell populations and the inhibition of neuro-QDOGLIIHUHQWLDWLRQ*HQHV'HY
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a pluripotent ES-cell-like state. Nature.
1DNDJDZD 0 *HQHUDWLRQ RI LQGXFHG pluripotent stem cells without Myc from PRXVH DQG KXPDQ ÀEUREODVWV 1DWXUH %LRWHFKQRO
3HWULFK $0 1DEKDQ & 6PLWK 60 MYC-associated and double-hit lympho- PDV $UHYLHZRISDWKRELRORJ\SURJQR-sis, and therapeutic approaches. Can-FHU
)HUQDQGH] 3& )UDQN 65 :DQJ / HW DO *HQRPLF WDUJHWV RI WKH KXPDQ F0\F SURWHLQ*HQHV'HY 71. Eilers MS, Schirm S, Bishop JM. The MYC
SURWHLQDFWLYDWHVWUDQVFULSWLRQRIWKHDO-pha-prothymosin gene. EMBO J. 1991;
$GKLNDU\6(LOHUV07UDQVFULSWLRQDOUHJXOD-tion and transforma$GKLNDU\6(LOHUV07UDQVFULSWLRQDOUHJXOD-tion by Myc proteins. 1DW5HY0RO&HOO%LRO 0DWH\DN 0. 2ED\D $- 6HGLY\ -0
F0\F UHJXODWHV F\FOLQ '&GN DQG &GNDFWLYLW\EXWDIIHFWVFHOOF\FOHSUR-gression at multiple independent points. 0RO&HOO%LRO
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.ODSSURWK . :LUWK 7 $GYDQFHV LQ WKH understanding of MYC-induced lym-SKRPDJHQHVLV %U - +DHPDWRO
76. Hermeking H, Eick D. Mediation of F0\FLQGXFHG DSRSWRVLV E\ S 6FL-HQFH
(LVFKHQ &0 :RR ' 5RXVVHO 0) HW DO $SRSWRVLV WULJJHUHG E\ 0\FLQGXFHG VXSSUHVVLRQ RI %FO; / RU %FO LV E\-passed during lymphomagenesis. Mol &HOO%LRO
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79. Chang TC, Yu D, Lee YS, et al. Wide-VSUHDG PLFUR51$ UHSUHVVLRQ E\ 0\F FRQWULEXWHVWRWXPRULJHQHVLV1DW*HQHW
80. Sander S, Bullinger L, Wirth T. Repressing the repressor: a new mode of MYC
ac-tion in lymphomagenesis. Cell Cycle.
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et al. N-myc can cooperate with ras to transform normal cells in culture. Proc 1DWO$FDG6FL86$ /RPEDUGL / 1HZFRPE (:
'DOOD)DYH-ra R. Pathogenesis of Burkitt lymphoma: H[SUHVVLRQRIDQDFWLYDWHGFP\FRQFR-JHQHFDXVHVWKHWXPRULJHQLFFRQYHUVLRQ RI (%9LQIHFWHG KXPDQ % O\PSKREODVWV &HOO
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lymphocytes and embryonic stem cells. &HOO
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