ABSTRACT
Myeloid leukemia in Down syndrome (ML-DS) clonally evolves from transient abnormal myelopoiesis (TAM), a preleukemic condition in DS newborns. To define mechanisms of leukemic transformation, we combined exome and targeted resequencing of 111 TAM and 141 ML-DS samples with functional analyses. TAM requires trisomy 21 and truncating mutations in GATA1; additional TAM variants are usually not pathogenic. By contrast, in ML-DS, clonal and subclonal variants are functionally required. We identified a recurrent and oncogenic hotspot gain-of-function mutation in myeloid cytokine receptor CSF2RB. By a multiplex CRISPR/Cas9 screen in an in vivo murine TAM model, we tested loss-of-function of 22 recurrently mutated ML-DS genes. Loss of 18 different genes produced leukemias that phenotypically, genetically, and transcriptionally mirrored ML-DS.
Subject(s)
Biomarkers, Tumor/genetics , Cell Transformation, Neoplastic/genetics , Chromosomes, Human, Pair 21 , Cytokine Receptor Common beta Subunit/genetics , Down Syndrome/genetics , GATA1 Transcription Factor/genetics , Leukemia, Myeloid/genetics , Leukemoid Reaction/genetics , Mutation , Animals , Disease Models, Animal , Disease Progression , Down Syndrome/diagnosis , GATA1 Transcription Factor/metabolism , Gene Expression Regulation, Leukemic , Genetic Predisposition to Disease , HEK293 Cells , Humans , Leukemia, Myeloid/diagnosis , Leukemia, Myeloid/pathology , Leukemoid Reaction/diagnosis , Mice, Inbred C57BL , Mice, Inbred NOD , Mice, Transgenic , Phenotype , Transcription, GeneticABSTRACT
Children with Down syndrome are at high risk to develop myeloid leukemia (ML-DS). Despite their excellent prognosis, children with ML-DS particularly suffer from severe therapy-related toxicities and for relapsed ML-DS the cure rates are very poor. Here we report the clinical course of one child with ML-DS treated with the histone deacetylase (HDAC) inhibitor vorinostat (suberoylanilide hydroxamic acid) after second relapse. The child had previously received conventional chemotherapy and stem cell transplantation, yet showed a remarkable clinical and hematologic response. Thus, HDAC inhibitor may represent an effective class of drugs for the treatment of ML-DS.
