Modelling the progression of a preleukemic stage to overt leukemia in children with Down syndrome

Introduction:

AML in children with Down syndrome (ML-DS) evolves from preceding transient abnormal myelopoiesis (TAM) by acquisition of unknown genetic lesions.

Methods:

Prevalence, impact and interplay of chosen mutations in ML-DS transformation were explored by lentiviral overexpression or CRISPR-Cas9 multiplex-knockout (MKO) approaches in human and murine HSPCs.

Results:

Sequencing of 252 patients showed that mutations in genes belonging to the cohesin-complex, histone modifying proteins or signaling pathways are most prevalent in ML-DS. Functional characterization revealed oncogenic properties of the newly identified recurrent CSF2RB mutation. Integrative CRISPR-Cas9 MKO in vivo assays recapitulated and underlined the transformative potential of the mutational spectrum detected in patients.

Conclusion:

Thus, by genetically characterizing and functionally dissecting the unique ML-DS mutational landscape we uncovered the genetic lesions that cooperate with mutated Gata1 in the fetal background in the pathogenesis of ML-DS.