en
Scientific article
English

Exome sequencing identifies putative drivers of progression of transient myeloproliferative disorder to AMKL in infants with Down syndrome

Published inBlood, vol. 122, no. 4, p. 554-561
Publication date2013
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.

Keywords
  • Cell Transformation, Neoplastic/genetics
  • Disease Progression
  • Down Syndrome/complications/genetics
  • Exome/genetics
  • Genetic Predisposition to Disease/genetics
  • Genome-Wide Association Study
  • Genomic Instability/genetics
  • High-Throughput Nucleotide Sequencing/methods
  • Humans
  • Infant
  • Infant, Newborn
  • Leukemia, Megakaryoblastic, Acute/complications/genetics/pathology
  • Microarray Analysis
  • Myeloproliferative Disorders/complications/genetics/pathology
  • Polymorphism, Single Nucleotide
  • Transcriptome
Citation (ISO format)
NIKOLAEV, Sergey Igorievich et al. Exome sequencing identifies putative drivers of progression of transient myeloproliferative disorder to AMKL in infants with Down syndrome. In: Blood, 2013, vol. 122, n° 4, p. 554–561. doi: 10.1182/blood-2013-03-491936
Main files (1)
Article (Published version)
accessLevelRestricted
Identifiers
ISSN of the journal0006-4971
567views
0downloads

Technical informations

Creation02/13/2014 5:41:00 PM
First validation02/13/2014 5:41:00 PM
Update time03/14/2023 8:59:39 PM
Status update03/14/2023 8:59:39 PM
Last indexation01/16/2024 9:18:34 AM
All rights reserved by Archive ouverte UNIGE and the University of GenevaunigeBlack