Foetal-specific contributors to infant MLL-AF4-driven Acute Lymphoblastic Leukaemia
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA703969 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13763200_1.fastq.gz | Fastqsanger.gz | |||
| SRR13763200_2.fastq.gz | Fastqsanger.gz | |||
| SRR13763201_1.fastq.gz | Fastqsanger.gz | |||
| SRR13763201_2.fastq.gz | Fastqsanger.gz | |||
| SRR13763202_1.fastq.gz | Fastqsanger.gz |
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Project description:As MLL-rearranged infant leukaemia is known to initiate in utero, we sought to identify developemntal genes expressed in foetal cells that may aid leukaemogenesis. Bulk RNA-Seq was therefore carried out on mouse and human foetal liver blood progenitors (lymphoid-primed multipotent progenitors [LMPPs] and haematopoietic stem cells/ multipotent progenitor cells [HSC/MPPs]) and compared with the same cell types isolated from developmentally later human cord blood and mouse adult bone marrow.
2021-10-07 | GSE167234 | GEO
Project description:MLL-AF4+ blasts from infant B-ALL, CB-derived CD34+CD38-CD19-CD33- HSC, CB-derived CD34+CD19+CD33- B-cell HPCs and CB-derived CD34+CD33+CD19- myeloid HPCs. We used microarray to estudy gene expression profile comparing ALL vs HSC, HPC and myeloid HPSC. We used highly FACS-purified (purity>98%) MLL-AF4+ blasts from infant B-ALL, CB-derived CD34+CD38-CD19-CD33- HSC, CB-derived CD34+CD19+CD33- B-cell HPCs and CB-derived CD34+CD33+CD19- myeloid HPCs. For each independent sample technical duplicates were always performed. Total RNA was extracted using TRIol reagent, and quantified on a Nanodrop spectrophotometer and Bioanalyzer. High-quality RNA was reverse transcribed and the obtained cDNA was used as a template to synthesize biotinylanted cDNA, then was fragmented and hybridized as duplicates/triplicates to HG-U133 plus2.0 GeneChips (Affymetrix) according to manufacturer's guideline.
2016-03-22 | E-GEOD-79450 | biostudies-arrayexpress
Project description:Chromatin accessibility was assessed by ATAC-Seq in lymphoid-primed multipotent progenitors (LMPPs) from human foetal livers (FLs) and mouse wild-type FLs as well as FLs from mouse embryos that express the oncofusion Mll-AF4 in the definitive blood system. The aim of this study was to establish whether overall chromatin accessibility at key haematopoietic sites and loci that have been linked to leukaemia are differentially accessible in human vs mouse LMPPs and whether this is altered by the expression of the Mll-AF4 oncofusion.
2021-05-28 | GSE168438 | GEO
Project description:MLL-AF4+ blasts from infant B-ALL, CB-derived CD34+CD38-CD19-CD33- HSC, CB-derived CD34+CD19+CD33- B-cell HPCs and CB-derived CD34+CD33+CD19- myeloid HPCs. We used microarray to estudy gene expression profile comparing ALL vs HSC, HPC and myeloid HPSC.
2016-03-22 | GSE79450 | GEO
Project description:MLL/AF4 fusion transcript knock-down time course in the MLL/AF4-positive B-cell precursor ALL cell line SEM using MLL/AF4 fusion site-specific siRNAs (siMLL/AF4). The aim was to identify genes responsive to MLL/AF4 expression modulation.
2018-07-21 | GSE71140 | GEO
Project description:Acute Lymphoblastic Leukemia (ALL) caused by chromosomal translocation involving the Mixed Lineage Leukemia (MLL) gene remains a poor prognosis disease, especially in infants. The most common MLL-rearrangement in infant ALL (iALL), MLL-AF4, originates in utero where the properties of fetal target cells likely provide a permissive landscape for transformation. We describe the first faithful MLL-AF4 iALL model derived by CRISPR-Cas9 genome editing of primary human fetal liver (FL) cells. Using this model, we demonstrate that H3K79me2/3 is increased during transformation as a direct consequence of MLL-AF4 binding, but correlates weakly with changes in gene expression. DOT1L, the only known H3K79 methyltransferase, does not form part of the MLL-AF4 complex. Instead, we identify PAF1 as a key protein recruited by the MLL-AF4 complex, which in turn can recruit DOT1L. These results explain the previously unclear link between MLL-AF4 binding and increased H3K79me2/3, and introduce an iALL-specific model for future drug studies.
2021-10-25 | GSE162032 | GEO
Project description:Infants diagnosed of precursor B-cell acute lymphoblastic leukemia (iB-ALL) presenting MLL-AF4 chromosomal rearrangement are at high risk of disease progression into fatal outcome. This specific subtype of pediatric leukemia constitutes a tough challenge in leukemia research, given the difficulties found when trying in vivo modelling. However, the understanding of mechanisms leading to proper lymphocyte generation may become of high utility in gaining deep insight on this malignancy. As we report here, the lack of HDAC7, a key transcriptional regulator in B lymphocyte differentiation, worsens the prognosis of iB-ALL patients. In fact, MLL-AF4+ iB-ALL patients with high expression of HDAC7 display an improved survival, partially mediated by the repression of oncogenes, such as c-MYC, and chemoresistance markers, like the ASNS enzyme. Accordingly, HDAC7 drastically reduces leukemic cells proliferation in MLL-AF4+ iB-ALL through the induction of apoptosis. Moreover, RNA sequencing of HDAC7-overexpressing cells has revealed that HDAC7 alters the genomic profiling of MLL-AF4+ iB-ALL cells towards that of healthy B-cell progenitors. In summary, the findings here reported highlight the role of HDAC7 in predicting prognosis of a lethal subtype of iB-ALL and open new clinical perspectives, since MLL-AF4+ iB-ALL infants would highly benefit from therapeutic options eventually restoring HDAC7 expression.
2021-06-04 | GSE151793 | GEO
Project description:Malignant transformation in a multipotential precursor has recently been shown to underlie mixed phenotype acute leukaemias. In contrast, and despite the conclusive demonstration that MLL-AF4 infant ALL arises in utero. In order to address this we purified haematopoietic stem/progenitor cell (HSPC) populations from four non-lineage switching presentation infant ALL cases and one ALL presentation which went on to lineage switch at relapse. The specific MLL-AF4 fusion event was determined in unsorted samples by LDI-PCR and identified in purified populations by nested PCR. In three cases where non-lineage restricted populations were able to be purified, MLL-AF4 was identified in the CD34+CD38-CD45RA+ population (LK228, LK230, LS01), the CD34+CD38-CD45RA-CD90- multipotential progenitor population (MPP, LS01) and even a candidate CD34+CD38-CD45RA-CD90+ haematopoietic stem cell (HSC) population (LK228) Interestingly, in a single non-switched MLL-AF9 case analysed for external comparison, the fusion was only identified in CD19+ blast/B cell populations, not in any HSPC population. Unexpectedly, we were also able to identify the presence of the MLL-AF4 fusion in apparently normally differentiated CD34-CD19/3-HLA-DR+CD14/11c+ monocytes/dendritic cells from the peripheral blood/bone marrow of 4/5 cases examined. This finding was further supported by single cell analysis of LS01PALL which identified the fusion in 2/22 CD34-CD19/3-HLA-DR+CD14/11c+ monocytes/dendritic cells analysed. Furthermore, the matched AML sample (LS01RAML) also contained MLL-AF4 positive mature T lymphoid cells. These data imply that MLL-AF4 does not impose a complete block on normal haematopoietic differentiation, and raise the question of what additional factors contribute to leukaemic lineage determination in the setting of the MLL-AF4 translocation. To examine the functional capacity of MLL-AF4 transformed precursor cells we generated a patient-derived xenograft model using NOD-scid/IL2Rγ-/- (NSG) mice. Serial xenotransplantation identified an MLL-AF4 positive clone persisting within the human CD34+CD38-CD45RA-CD90+ compartment across four generations of mice, confirming self-renewal of this population. Together these data identify an early multipotent progenitor or HSC as the putative cell of origin for MLL-AF4 ALL. Furthermore, they demonstrate that MLL-AF4, uniquely amongst MLL fusion genes, imposes a profound lymphoid bias on the developing leukemia but without completely abolishing broader, non-malignant, haematopoietic differentiation.
2020-04-21 | GSE132396 | GEO
Project description:Malignant transformation in a multipotential precursor has recently been shown to underlie mixed phenotype acute leukaemias. In contrast, and despite the conclusive demonstration that MLL-AF4 infant ALL arises in utero. In order to address this we purified haematopoietic stem/progenitor cell (HSPC) populations from four non-lineage switching presentation infant ALL cases and one ALL presentation which went on to lineage switch at relapse. The specific MLL-AF4 fusion event was determined in unsorted samples by LDI-PCR and identified in purified populations by nested PCR. In three cases where non-lineage restricted populations were able to be purified, MLL-AF4 was identified in the CD34+CD38-CD45RA+ population (LK228, LK230, LS01), the CD34+CD38-CD45RA-CD90- multipotential progenitor population (MPP, LS01) and even a candidate CD34+CD38-CD45RA-CD90+ haematopoietic stem cell (HSC) population (LK228) Interestingly, in a single non-switched MLL-AF9 case analysed for external comparison, the fusion was only identified in CD19+ blast/B cell populations, not in any HSPC population. Unexpectedly, we were also able to identify the presence of the MLL-AF4 fusion in apparently normally differentiated CD34-CD19/3-HLA-DR+CD14/11c+ monocytes/dendritic cells from the peripheral blood/bone marrow of 4/5 cases examined. This finding was further supported by single cell analysis of LS01PALL which identified the fusion in 2/22 CD34-CD19/3-HLA-DR+CD14/11c+ monocytes/dendritic cells analysed. Furthermore, the matched AML sample (LS01RAML) also contained MLL-AF4 positive mature T lymphoid cells. These data imply that MLL-AF4 does not impose a complete block on normal haematopoietic differentiation, and raise the question of what additional factors contribute to leukaemic lineage determination in the setting of the MLL-AF4 translocation. To examine the functional capacity of MLL-AF4 transformed precursor cells we generated a patient-derived xenograft model using NOD-scid/IL2Rγ-/- (NSG) mice. Serial xenotransplantation identified an MLL-AF4 positive clone persisting within the human CD34+CD38-CD45RA-CD90+ compartment across four generations of mice, confirming self-renewal of this population. Together these data identify an early multipotent progenitor or HSC as the putative cell of origin for MLL-AF4 ALL. Furthermore, they demonstrate that MLL-AF4, uniquely amongst MLL fusion genes, imposes a profound lymphoid bias on the developing leukemia but without completely abolishing broader, non-malignant, haematopoietic differentiation.
2020-04-21 | GSE130142 | GEO
Project description:Purpose: To investigate metabolic adaptation of leukaemia in two different microenvironments: central nervous system and spleen Methods: The SEM (MLL-AF4) cell-line representing a high-risk subtype was used. Cells were transplanted into immunodeficient mice. CNS tropism was demonstrated and blasts invaded the leptomeninges in a timeframe ranging from 4 to 5 weeks. At experimental endpoint, blasts were retrieved from the CNS and periphery (spleen), and their gene expression profiles were compared using RNA-sequencing. The raw reads were pre-processed with Cutadapt v.1.5 and Sickle v.0.940 software. Transcript expression quantification was performed using Kallisto v.0.42.4 software against combined human and mouse transcriptomes, Ensembl GRCh38.79 and GRCm38.78, respectively. Read counts related to human transcripts were collected, rounded, and summarized into gene specific read counts. Gene-based differential expression analysis was done with DESeq2 R-package. Preprocessed RNA expression data from RNA sequencing was analysed further using single sample gene set enrichment analysis (ssGSEA). Results: The human SEM cells’ gene expression profiles clustered according to site of colonization in the transplanted mice; CNS versus spleen. The top differentially expressed genes were associated with cellular metabolism or stress responses. ssGSEA analysis identified positive correlation of lipid and lipoprotein metabolism signatures in CNS-derived cells, with particular propensity towards fatty acid synthesis. On the other hand, oxidative phosphorylation processes, linked to fatty acid degradation, were negatively correlated with CNS involvement and enriched in SEM cells from the spleen of transplanted mice. Conclusions: We demonstrate that leukaemic cells undergo widespread dynamic rewiring of metabolism when switching from bone marrow to CNS microenvironments, resulting in altered therapeutic vulnerabilities. We observed a strong fatty-acid synthesis signature in CNS leukaemia, highlighting Stearoyl-CoA desaturase (SCD1) as a key player.
2020-07-08 | GSE135113 | GEO