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Mapping the Cellular Origin and Early Evolution of Down Syndrome Leukemogenesis [CUT&RUN]

ABSTRACT: Children with Down syndrome have a 150-fold increased risk of developing myeloid leukemia. As Down syndrome leukemogenesis initiates during fetal development, we sought to characterize the cellular mechanisms of preleukemic initiation and leukemic progression using CRISPR/Cas9-mediated gene editing in human disomic and trisomic fetal liver hematopoietic cells and xenotransplantation. Compared to disomic fetal liver, trisomy 21 initiated atypical fetal hematopoiesis, in part through up-regulation of chromosome 21 miRNAs. GATA1 mutations caused transient preleukemia only when introduced into trisomy 21 long-term hematopoietic stem cells. By contrast, progression to leukemia was independent of trisomy 21 and originated in a wide spectrum of stem and progenitor cells through additional mutations in cohesin genes such as STAG2. CD117+ cells mediated the propagation and progression of the preleukemic and leukemic disease. Treatment with small molecule CD117/KIT inhibitors efficiently targeted preleukemic stem cells and blocked progression to leukemia; thereby laying the groundwork for early prevention strategies in Down syndrome newborns.

ORGANISM(S): Homo sapiens

PROVIDER: GSE160093 | GEO | 2021/07/08

REPOSITORIES: GEO

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Mapping the Cellular Origin and Early Evolution of Down Syndrome Leukemogenesis [miRNA-Seq]

Project description:Children with Down syndrome have a 150-fold increased risk of developing myeloid leukemia. As Down syndrome leukemogenesis initiates during fetal development, we sought to characterize the cellular mechanisms of preleukemic initiation and leukemic progression using CRISPR/Cas9-mediated gene editing in human disomic and trisomic fetal liver hematopoietic cells and xenotransplantation. Compared to disomic fetal liver, trisomy 21 initiated atypical fetal hematopoiesis, in part through up-regulation of chromosome 21 miRNAs. GATA1 mutations caused transient preleukemia only when introduced into trisomy 21 long-term hematopoietic stem cells. By contrast, progression to leukemia was independent of trisomy 21 and originated in a wide spectrum of stem and progenitor cells through additional mutations in cohesin genes such as STAG2. CD117+ cells mediated the propagation and progression of the preleukemic and leukemic disease. Treatment with small molecule CD117/KIT inhibitors efficiently targeted preleukemic stem cells and blocked progression to leukemia; thereby laying the groundwork for early prevention strategies in Down syndrome newborns.

2021-07-08 | GSE160095 | GEO

Transcription profiling by array of the Ts(1716)65Dn Down syndrome mouse model bone marrow lineage- c-Kit+ Sca-1+ (LSK), CMP, GMP and MEP progenitor cell populations, in which trisomy of Erg was specifically reduced to disomy using the Mld2 allele

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Project description:Trisomy of chromosome 21, the genetic cause of Down syndrome, has the potential to alter expression of genes on chromosome 21, as well as other locations throughout the genome. These transcriptome changes are likely to underlie the Down syndrome clinical phenotypes. We have employed RNA-seq to undertake an in-depth analysis of transcriptome changes resulting from trisomy of chromosome 21, using induced pluripotent stem cells (iPSCs) derived from a single individual with Down syndrome. These cells were originally derived by Li et al, who genetically targeted chromosome 21 in trisomic iPSCs, allowing selection of disomic sibling iPSC clones. Analyses were conducted on trisomic/disomic cell pairs maintained as iPSCs or differentiated into cortical neuronal cultures.

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Role of trisomy 21, GATAs mutation and associated mutations in the development of a DS-AMKL model from IPSC: Cut&Tag

Project description:Acute megakaryoblastic leukemia of Down syndrome (DS-AMKL) is a model of clonal evolution from a preleukemic transient myeloproliferative disorder requiring both a trisomy 21 (T21) and a GATA1s mutation to a leukemia driven by additional driver mutations. We modelled this leukemic evolution through stepwise gene editing of GATA1s, SMC3+/- and MPLW515K providing 20 different trisomy or disomy 21 iPSC clones. Cut&Tag against GATA1 was performed on CD41+CD42+ megakaryocytes obtained after 18 days of differentiation of the IPSC clones. 500,000 CD41+CD42+ MK sorted cells were used to analyze GATA1 and GATA1s chromatin occupancy using the CUT&Tag-IT Assay Kit (Active Motif) according to the manufacturer recommendations. Briefly, cells were bound to Concanavalin A-Coated Beads and incubated with primary anti-GATA1 antibody in buffer with Protease Inhibitor Cocktail and 5% digitonine overnight at 4°C under rotation. The Guinea Pig anti-rabbit secondary antibody was incubated in Dig-Wash buffer for 1 hour at RT under rotation. After 3 washes, the CUT&Tag-IT™ Assembled pA-Tn5 Transposomes (1:100) were added for 1 hour at RT under rotation and tagmentation was performed during 1 hour at 37°C. DNA was purified and libraries were generated by PCR. The final libraries were purified, pooled together in equal concentrations and subjected to paired-end sequencing (100 cycles: 2x50) in Novaseq-6000 sequencer (Illumina) at Gustave Roussy.

2022-09-30 | E-MTAB-11032 | biostudies-arrayexpress

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Project description:Acute megakaryoblastic leukemia of Down syndrome (DS-AMKL) is a model of clonal evolution from a preleukemic transient myeloproliferative disorder requiring both a trisomy 21 (T21) and a GATA1s mutation to a leukemia driven by additional driver mutations. We modelled this leukemic evolution through stepwise gene editing of GATA1s, SMC3+/- and MPLW515K providing 20 different trisomy or disomy 21 iPSC clones. Single cell analysis was performed on hematopoietic cells obtained from IPSC clones after 13 days of differentiation. Sample preparation was done at room temperature. Single-cell suspensions were loaded onto a Chromium Single Cell Chip (10x Genomics) according to the manufacturer’s instructions for co-encapsulation with barcoded Gel Beads at a target capture rate of ~10,000 individual cells per sample. Captured mRNAs were barcoded during cDNA synthesis using the Chromium Next GEM Single Cell 3' GEM, Library & Gel Bead Kit v3.1 (10X Genomics) according to the manufacturer’s instructions. All samples were processed simultaneously with the Chromium Controller (10X Genomics) and the resulting libraries were prepared in parallel in a single batch. We pooled all of the libraries for sequencing in a single SP Illumina flow cell. All of the libraries were sequenced with an 8-base index read, a 28-base Read1 containing cell-identifying barcodes and unique molecular identifiers (UMIs), and a 91-base Read2 containing transcript sequences on an Illumina NovaSeq 6000.

2022-09-29 | E-MTAB-11036 | biostudies-arrayexpress

Large-scale study suggests effects of trisomy 21 on fetal neurodevelopment may be more subtle than variability between organoids and isogenic lines

Project description:This study examines cortical organoids generated from a panel of isogenic trisomic and disomic iPSC lines (subclones) as a model of early fetal brain development in Down syndrome. An initial experiment comparing organoids from one trisomic and one disomic line showed many genome-wide transcriptomic differences and modest differences in cell-type proportions, suggesting there may be a neurodevelopmental phenotype that is due to trisomy of chr 21. To better control for multiple sources of variation, we undertook a highly robust study of ∼1,200 organoids using an expanded panel of six all-isogenic lines, three disomic, and three trisomic. The power of this experimental design was indicated by strong detection of the ∼1.5- fold difference in chr21 genes. However, the numerous expression differences in non-chr21 genes seen in the smaller experiment fell away, and the differences in cell-type representation between lines did not correlate with trisomy 21. Results suggest that the initial smaller experiment picked up differences between small organoid samples and individual isogenic lines, which “averaged out” in the larger panel of isogenic lines. Our results indicate that even when organoid and batch variability are better controlled for, variation between isogenic cell lines (even subclones) may obscure, or be conflated with, subtle neurodevelopmental phenotypes that may be present in ∼2nd trimester DS brain development. Interestingly, despite this variability between organoid batches and lines, and the “fetal stage” of these organoids, an increase in secreted Aβ40 peptide levels—an Alzheimer-related cellular phenotype—was more strongly associated with trisomy 21 status than were neurodevelopmental shifts in cell-type composition.

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Project description:Gene expression was measured in trisomy 21 and trisomy 13 human fetal samples. For TS21, regions assayed were cerebrum, cerebellum, heart, and cerebrum-derived astrocyte cell lines. Keywords = trisomy 21 Keywords = Down syndrome Keywords = aneuploidy Keywords = brain Keywords = heart Keywords = trisomy 13 Keywords: other

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Project description:Aneuploidy and structural aberrations affecting chromosome 21 (Hsa21) are the most frequent in cytogentic events in acute myeloid leukemia. However, it remains unclear why leukemic blasts select for amplifications of Hsa21 or parts of it and why children with Down syndrome (i.e. trisomy 21) are at a high risk of developing leukemia. Here, we propose that disequilibrium of the RUNX1 isoforms and resultant RUNX1A dominance are key to trisomy 21-associated leukemogenesis. Using a Hsa21-focussed CRISPR-Cas9 screen, we uncovered a strong and specific RUNX1 dependency in myeloid leukemia associated with Down syndrome (ML-DS). High levels of RUNX1A – as seen in ML-DS – synergized with the pathognomonic Gata1s mutation in ML-DS pathogenesis, an effect that was reversed upon restoration of the normal RUNX1A:RUNX1C equilibrium. Mechanistically, RUNX1A displaces RUNX1C from its endogenous binding sites and recruits the MYC cofactor MAX to induce oncogenic programs and perturb normal differentiation. This presents a therapeutic vulnerability that can be exploited by interfering with MYC:MAX dimerization. Our study highlights the importance of alternative splicing in leukemogenesis, and paves the way for developing specific and targeted therapies for ML-DS as well as for other leukemias with Hsa21 aneuploidy or RUNX1 isoform disequilibrium.

2023-05-10 | PXD030616 | Pride

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