Abstract
Simple SummaryLeukaemia occurs when specific mutations promote aberrant transcriptional and proliferation programs, which drive uncontrolled cell division and inhibit the cell’s capacity to differentiate. In this review, we summarize the most frequent genetic lesions found in myeloid leukaemia of Down syndrome, a rare paediatric leukaemia specific to individuals with trisomy 21. The evolution of this disease follows a well-defined sequence of events and represents a unique model to understand how the ordered acquisition of mutations drives malignancy.Children with Down syndrome (DS) are particularly prone to haematopoietic disorders. Paediatric myeloid malignancies in DS occur at an unusually high frequency and generally follow a well-defined stepwise clinical evolution. First, the acquisition of mutations in the GATA1 transcription factor gives rise to a transient myeloproliferative disorder (TMD) in DS newborns. While this condition spontaneously resolves in most cases, some clones can acquire additional mutations, which trigger myeloid leukaemia of Down syndrome (ML-DS). These secondary mutations are predominantly found in chromatin and epigenetic regulators—such as cohesin, CTCF or EZH2—and in signalling mediators of the JAK/STAT and RAS pathways. Most of them are also found in non-DS myeloid malignancies, albeit at extremely different frequencies. Intriguingly, mutations in proteins involved in the three-dimensional organization of the genome are found in nearly 50% of cases. How the resulting mutant proteins cooperate with trisomy 21 and mutant GATA1 to promote ML-DS is not fully understood. In this review, we summarize and discuss current knowledge about the sequential acquisition of genomic alterations in ML-DS.
Highlights
Trisomy 21 is the most common chromosomal disorder in humans and is the genetic basis of Down syndrome (DS) [1]
acute myeloid leukaemia (AML) is a heterogeneous group of myeloid leukaemias that originate from clones of haematopoietic stem and progenitor cells (HSPCs) and myeloid lineage precursors carrying genetic mutations that alter cell proliferation and compromise differentiation
While the aberrant foetal haematopoietic differentiation of trisomy 21 may provide a basis for the selective advantage of clones with GATA1 mutations, it is yet unclear why mutations in cohesin and CTCF are so abundant in myeloid leukaemia of Down syndrome (ML-DS)
Summary
Trisomy 21 is the most common chromosomal disorder in humans and is the genetic basis of Down syndrome (DS) [1]. This multisystem disorder results in numerous phenotypic features, including craniofacial abnormalities and cognitive impairment [2]. AML is a heterogeneous group of myeloid leukaemias that originate from clones of haematopoietic stem and progenitor cells (HSPCs) and myeloid lineage precursors carrying genetic mutations that alter cell proliferation and compromise differentiation. In myeloid leukaemia of Down syndrome (ML-DS), most. In myeloid leukaemia of Down synd(AcAraoMMsmeLKsMeMLpinL)Lh(,-Mwe-aDDnrLhSoaS-itrcDiyeishsSpsc)mcui,hchbauaamtlrtyrlaayapoctcseirtotteeoenrflfrciseizAazcceseMtodedasmLcbbpuyipynrtheoawaemmndhdoiiiesisctsgeythtiapimnmnkiccaceutatrgitilvylavayoetkeiboammlrrnaeyussufoltlcelticotciciy-mt-sltsetiptecauerpckmpouametaeeevtvmiuosoemlriluaamuett(tiigAeiooaognnMkna.akiKirnanyLrowyw)b,ohlahcaiyicrscthatihicrceimittslieauissutbuakatrlyalawweptmiaeaoyynioass.f pprreecceeddeeddbbyyaapprree--lleeuukkaaeemmiiccccoonnddiittiioonnkknnoowwnnaassttrraannssieiennttaabbnnoorrmmaallmmyyeeloloppooieiessisis(T(TAAMM)) oorrttrraannssiieennttmmyyeelloopprroolliiffeerraattiivveeddiissoorrddeerr((TTMMDD))[[66,,88]] ((FFiigguurree 11)). Tfrheiqsuheingchyfrisequuneenxcpyecisteudn, eexsppeeccitaeldly, efsopreCcTiaCllFy wfohricChTiCsFrawrehliychmiustraateredlyinmAuMtaLtedorinotAheMr Lmoyrelootihdemr maliygenloanidcimesa. lMigonraenocvieesr., cMhroormeoavtienr, mchordoimfieartsinsumcohdaisfieErZsHsu2cahreasmEoZreHf2reaqreuemnotlryemfreuqtauteendtliyn mMuLt-aDteSdthinanMiLn-ADMS tLh.aSniginnaAllMingL. pSaigthnwalaliynmg uptaatthiownasyamreumtaotsitolnysfoaurendmionsrtleycefpoutonrds ainndremceepmtobresrsaonfdthmeeJmanbuesrskionfatshee-sJiagnnuals tkrainnassdeu-cstigionnalantrdanascdtiuvcattioornoafnthdeatcrtaivnasctorirpotifotnhe(JAtraKn-SscTrAipTt)iosnig(nJAalKlin-SgTcAaTsc)asdigen, aaslliwngellcaassicnatdhee, RasAwS eplal tahswinayt.hTehReAseSmpuatahtwioanys. mThaeysienmteruftearteioonrscmooapyerinaterwfeirteh oarltecoreodpesirgantealwlinitgh paaltehrwedayssiginaDlliSn.gInpagtehnweraayls, hinowDeSv. eInr, gtheneeirnatle,rhpolawyebvetrw, teheeninthteerpthlareyebgeetwneeteicn etlheemtehnretse cgoemnpetriicsienlgemthenistsdciosemasper—isitnrigsothmisyd2is1e, aGseA—TAtr1isommuyta2ti1o,nGsAaTnAd1 smeucotantdioanrys amnudtsaeticoonnsd—arisy pmouotralytiounnsd—eristpooodr.lHy eurned, werestporoodv. iHderaen, woveeprvroievwideofatnheovceurrvrieenwt konfothwelecdugrreenont khnoowwtlhedesgee eolenmheonwtsthmeasye eplreommeonttes MmLay-DpSr.omote ML-DS
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