0442083098a9b0cb53c55ade674fd933 cancers-13-04144.pdf 73fc12e70ab74dd82323b40d4cb700488e21dc3f cancers-13-04144.pdf 37c764b2d4a7bfeb9c0dcdba858893128d50bf45e9dfe99bd45680572e77fe94 cancers-13-04144.pdf Title: The Mutational Landscape of Myeloid Leukaemia in Down Syndrome Subject: 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. Keywords: myeloid leukaemia; Down syndrome; trisomy 21; acute megakaryoblastic leukaemia (AMKL); transcription; chromatin; signalling Author: Carini Picardi Morais de Castro, Maria Cadefau and Sergi Cuartero Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Wed Aug 18 03:04:55 2021 CEST ModDate: Wed Aug 18 03:14:11 2021 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 18 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1129434 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- ZCKUBF+URWPalladioL-Ital Type 1 Custom yes yes no 10 0 IDXTLY+URWPalladioL-Bold Type 1 Custom yes yes no 15 0 YWPRIA+URWPalladioL-Roma Type 1 Custom yes yes no 19 0 LCJEVJ+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 28 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 45 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 49 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 53 0 BCDEEE+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 70 0 BCDFEE+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 74 0 BCDGEE+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 78 0 BCDHEE+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 82 0 FMUVYS+URWPalladioL-BoldItal Type 1 Custom yes yes no 94 0 IOLAWT+PazoMath-Italic Type 1 Builtin yes yes no 101 0 BCDEEE+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 113 0 BCDFEE+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 117 0 BCDGEE+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 121 0 BCDHEE+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 125 0 BCDKEE+PalatinoLinotype-Italic CID TrueType Identity-H yes yes yes 132 0 WLKZXL+VnURWPalladioL Type 1 Custom yes yes no 155 0 LHCXDL+EURM10 Type 1 Builtin yes yes no 173 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-06-30 02:38:45 CEST RepresentationInformation: cancers-13-04144.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-02-09 18:19:43 CET Size: 1129434 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 756 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: Altered Haematopoiesis in Down Syndrome Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Item: Title: Mutations in GATA1 Cause a Transient Myeloproliferative Disorder Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: Spectrum of Mutations Driving the Transition from TMD to ML-DS Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Children: Item: Title: Mutations in Transcriptional Regulators and Chromatin Modifiers Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Children: Item: Title: Mutations in the Cohesin Complex Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Mutations in CTCF Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Mutations in PRC2 Members Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Altered Signalling Pathways in ML-DS Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Children: Item: Title: Mutations in the JAK-STAT Pathway Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: Mutations in RAS Members Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Info: Title: The Mutational Landscape of Myeloid Leukaemia in Down Syndrome Author: Carini Picardi Morais de Castro, Maria Cadefau and Sergi Cuartero Subject: 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. 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