Mechanisms of Progression of Myeloid Preleukemia to Transformed Myeloid Leukemia in Children with Down Syndrome.
(2019) Cancer Cell — Vol. 36, n° 2, p. 123-138 (2019)
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- 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. [...]
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Labuhn, M., Perkins, K., Matzk, S., Varghese, L., Garnett, C., Papaemmanuil, E., Metzner, M., Kennedy, A., Amstislavskiy, V., Risch, T., Bhayadia, R., Samulowski, D., Hernandez, D. C., Stoilova, B., Iotchkova, V., Oppermann, U., Scheer, C., Yoshida, K., Schwarzer, A., et al. (2019). Mechanisms of Progression of Myeloid Preleukemia to Transformed Myeloid Leukemia in Children with Down Syndrome. Cancer Cell, 36(2), 123-138. https://doi.org/10.1016/j.ccell.2019.06.007 (Original work published 2019)