Functional and molecular characterization of oncogenic dependencies on chromosome 21 in Down syndrome-associated myeloid leukemia

Introduction:

Transient abnormal myelopoiesis (TAM) and myeloid leukemia in children with Down syndrome (ML-DS) has its basis in trisomy 21 and the GATA1 s mutation. However, the molecular background and potentially targetable dependencies of this interaction remain to be elucidated.

Methods & Results:

In order to identify targetable dependencies in ML-DS, located on chromosome 21 (hsa21), we carried out a CRISPR-Cas9 screening, comprising all coding genes on hsa21. Following high-throughput screening in ML-DS and non- DS-AML cell lines, candidates were individually validated by flow cytometry-based depletion assays. These assays outlined six candidates strongly inhibiting leukemic cell growth in all cell lines, as well as two AMKL-specific candidates and four DS-AMKL specific candidates. Further analysis of the selected candidates underlined impact on cell cycle and apoptosis.

Conclusions:

Our hsa21-CRISPR-Cas9 screening enabled us to identify novel factors potentially involved in malignant hematopoietic development. Molecular analysis of these candidates will drive both understanding and treatment of TAM/ML-DS in the future.