Mapping the cellular origin and early evolution of leukemia in Down syndrome

Abstract

Children with Down syndrome have a 150-fold increased risk of developing myeloid leukemia, but the mechanism of predisposition is unclear. Because Down syndrome leukemogenesis initiates during fetal development, we characterized the cellular and developmental context of preleukemic initiation and leukemic progression using gene editing in human disomic and trisomic fetal hematopoietic cells and xenotransplantation. GATA binding protein 1 (GATA1) mutations caused transient preleukemia when introduced into trisomy 21 long-term hematopoietic stem cells, where a subset of chromosome 21 microRNAs affected predisposition to preleukemia. By contrast, progression to leukemia was independent of trisomy 21 and originated in various stem and progenitor cells through additional mutations in cohesin genes. CD117+/KIT proto-oncogene (KIT) cells mediated the propagation of preleukemia and leukemia, and KIT inhibition targeted preleukemic stem cells.

The Mutational Landscape of Myeloid Leukaemia in Down Syndrome

“…This might also be the case in ML-DS, since the RUNX1 gene resides on chromosome 21 and NRAS mutations are frequently found in the disease. Similar to the case of CTCF, EZH2 knock-out foetal liver progenitors with trisomy 21 and GATA1s expression did not drive leukemic transformation upon transplantation in mice [27]. This supports the hypothesis that EZH2 mutations act in cooperation with additional mutations in ML-DS.…”

“…As in the case of cohesin mutations, the unusually high frequency found in ML-DS suggests that the partial absence of CTCF function may cooperate with the dosage imbalance of chromosome 21 genes, with specific megakaryocytic transcriptional regulators, or with both. Unlike cohesin knock-out, however, CTCF knock-out trisomic GATA1s progenitors from foetal liver did not drive leukemic transformation upon transplantation in mice [27], suggesting that cohesin and CTCF mutations may not promote the same leukaemogenic effects, and that CTCF mutation may require additional events on top of GATA1 mutations. Further studies set in a DS genetic background are needed to elucidate the role of CTCF in this disease and to identify actionable targets.…”

“…Importantly, a CRISPR knock-out screen in mice with a disomic genetic background did not show increased expansion of cohesin knock-out cells, suggesting that trisomy 21 may increase their leukaemogenic potential [21]. On the other hand, CRISPR/Cas9 editing in trisomy 21 foetal liver progenitors indicates that, while trisomy 21 is required for pre-leukemic initiation by GATA1s, it is dispensable for leukemic progression upon STAG2 knock-out [27].…”

“…This results in an expansion of megakaryocyte-erythroid progenitors (MEPs) and a decrease in granulocytemacrophage progenitors (GMP). In addition, B-cell differentiation is impaired [22][23][24][25][26][27]. The mechanisms by which the extra copy of chromosome 21 alters normal blood production remain unclear.…”

“…All TMD and ML-DS cases carry somatic mutations in GATA1 resulting in the introduction of a premature stop codon which promotes the exclusive translation of GATA1s [49]. Mechanistically, the long and short GATA1 isoforms have similar but non-identical binding patterns on the genome [27,[50][51][52]. MEP-specific genes and enhancers are differently bound by the two isoforms, which could explain the skewed differentiation profile of GATA1s-expressing cells.…”