| First Author | Labuhn M | Year | 2019 |
| Journal | Cancer Cell | Volume | 36 |
| Issue | 2 | Pages | 123-138.e10 |
| PubMed ID | 31303423 | Mgi Jnum | J:278960 |
| Mgi Id | MGI:6359642 | Doi | 10.1016/j.ccell.2019.06.007 |
| Citation | Labuhn M, et al. (2019) Mechanisms of Progression of Myeloid Preleukemia to Transformed Myeloid Leukemia in Children with Down Syndrome. Cancer Cell 36(2):123-138.e10 |
| abstractText | 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. |
