SpotlightExonsofLeukemiaSuppressorGenes:CreativeAssemblyRequiredMuktaAsnani1andAndreiThomas-Tikhonenko1,2,*Alternativesplicing(AS)hasmanyimportantrolesinthepathogene-sisofleukemia.Recentpaperssuggestthatoneofitskeyaspectsisexclusionof30-terminalexonsinfavorofprematureterminationusingintronicpolyadenylationsignals.ThisprocessgeneratesleukemiasuppressorisoformswithtruncatedCterminiandactinginloss-of-functionordominant-negativemanners.Theadventofnext-generationsequenc-ingapproachestoanalyzecancergenomesatthesingle-nucleotidereso-lutionhasrevolutionizedourunderstand-ingoftumorpathobiologyandledtotheidentificationofcancerdriversrecurrentlyaffectedbygain-of-function(oncogenes)andloss-of-function(tumor-suppressorgenes,orTSGs)mutations.Whileinmanyadultsolidcancersthemutationalloadishigh(hundredsofgeneticeventspersample),hematologicmalignancies(e.g.,pediatricandadultleukemias)aregeneticallyquiet,oftenwithnomorethanoneknownoncogenicdriverpersampleandnoevidenceofTSGinactivationatthegenomiclevel.Thisextremeparsi-monycreatesaconundrum:howdoesapreleukemiccellmanagetoeffectsomuchmalignantchangewithsolittlegeneticdiversity?OnepossibleansweristhatitsTSGscouldbesilencedbyepigeneticevents,forexampleDNAorhistonemethylation.Yetthesemecha-nismsarenotprevalentincommonlym-phoidmalignancies,suchaschroniclymphocytic(CLL)andBcellacutelym-phoblastoid(B-ALL)leukemias.Addition-ally,epigeneticmechanismstypicallyaffectlargeswathsofthegenomewellbeyondindividualTSGs,makingestab-lishingthecausationachallenge.Overthepastdecade,tworelatedbutdistinctpost-transcriptionalmechanismsofexonselection[ASandalternativepolyadeny-lation(APA)]haveemerged,whichactontargettranscriptswithpinpointaccuracy.Theyaffectbothcodingandnoncodingexonsandresultingreatertranscriptomeandproteomediversity,whichfrequentlyconfersgrowthadvantageuponleuke-miccells(Figure1).ASisawell-recognizedmRNAmaturationmechanism,whichgainedparticularprominenceintheleukemiafieldfollowingthediscoveryin2011ofdrivermutationsingenesencodingkeysplice...
