title: Exome sequencing identifies putative drivers of progression of transient myeloproliferative disorder to AMKL in infants with Down syndrome.
abstract: Some neonates with Down syndrome (DS) are diagnosed with self-regressing transient myeloproliferative disorder (TMD), and 20% to 30% of those progress to acute megakaryoblastic leukemia (AMKL). We performed exome sequencing in 7 TMD/AMKL cases and copy-number analysis in these and 10 additional cases. All TMD/AMKL samples contained GATA1 mutations. No exome-sequenced TMD/AMKL sample had other recurrently mutated genes. However, 2 of 5 TMD cases, and all AMKL cases, showed mutations/deletions other than GATA1, in genes proven as transformation drivers in non-DS leukemia (EZH2, APC, FLT3, JAK1, PARK2-PACRG, EXT1, DLEC1, and SMC3). One patient at the TMD stage revealed 2 clonal expansions with different GATA1 mutations, of which 1 clone had an additional driver mutation. Interestingly, it was the other clone that gave rise to AMKL after accumulating mutations in 7 other genes. Data suggest that GATA1 mutations alone are sufficient for clonal expansions, and additional driver mutations at the TMD stage do not necessarily predict AMKL progression. Later in infancy, leukemic progression requires "third-hit driver" mutations/somatic copy-number alterations found in non-DS leukemias. Putative driver mutations affecting WNT (wingless-related integration site), JAK-STAT (Janus kinase/signal transducer and activator of transcription), or MAPK/PI3K (mitogen-activated kinase/phosphatidylinositol-3 kinase) pathways were found in all cases, aberrant activation of which converges on overexpression of MYC.
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
authors.forename: Sergey I
authors.initials: SI
authors.lastname: Nikolaev
authors.forename: Federico
authors.initials: F
authors.lastname: Santoni
authors.forename: Anne
authors.initials: A
authors.lastname: Vannier
authors.forename: Emilie
authors.initials: E
authors.lastname: Falconnet
authors.forename: Emanuela
authors.initials: E
authors.lastname: Giarin
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Basso
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoischen
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.forename: Jurgen
authors.initials: J
authors.lastname: Groet
authors.forename: Dean
authors.initials: D
authors.lastname: Nizetic
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
mesh_terms: D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D018450:Disease Progression; D004314:Down Syndrome / Q000150:complications / Q000235:genetics*; D059472:Exome / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D042822:Genomic Instability / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007947:Leukemia, Megakaryoblastic, Acute / Q000150:complications / Q000235:genetics* / Q000473:pathology; D046228:Microarray Analysis; D009196:Myeloproliferative Disorders / Q000150:complications / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D059467:Transcriptome