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Series GSE90655 Query DataSets for GSE90655
Status Public on Dec 20, 2016
Title Clonal conversion of B-lymphoid leukemia reveals cross-lineage transfer of malignant states.
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
Summary Even though leukemia is considered as confined to one specific hematopoietic cell type, cases of acute leukemia of ambiguous lineage and patients relapsing in phenotypically altered disease suggest that a malignant state may be transferred between lineages. Because B-cell leukemia is associated with mutations in transcription factors of importance for stable preservation of lineage identity we here investigated the potential lineage plasticity of leukemic cells. We report that primary pro-B leukemia cells from mice carrying heterozygous mutations in either of or both the Pax5 and Ebf1 gene, commonly mutated in human leukemia, can be converted into T-lineage leukemia cells. Even though the conversion process involved global changes in gene expression and lineage restricted epigenetic reconfiguration, the malignant phenotype of the cells was preserved enabling them to expand as T-lineage leukemia cells in vivo. Furthermore, while the transformed pro-B cells displayed plasticity towards myeloid lineages, the converted cells failed to cause myeloid leukemia after transplantation. These data provide evidence that a malignant phenotype can be transferred between hematopoietic lineages. This has important implications for modern cancer medicine because lineage targeted treatment of leukemia patients can be predicted to provoke the emergence of phenotypically altered sub-clones causing clinical relapse.
 
Overall design ATAC-seq: Briefly, for T cell conditions primary leukemic ProB cells from mouse transheterozygote for Ebf1 +/- Pax5+/- (TH-LN683) were cocultured either on OP9 or OP9-DL1, CD19+Thy1.2- (Day2), CD19+Thy1.2+ (Day6) and CD19-Thy1.2+ (Day 14) cells were sorted. For myeloid conditions TH-LN381 cells were transduced with pMIG or C/EBPα-ER-pMIG and CD19+CD11b- (Day 1), CD19+CD11b+ (Day 2), CD19-CD11b+ (Day 5) were sorted. Lineage-KIT+Sca1+ (LSK) cells from Wt mouse were cultured either on B or T or Myeloid conditions and the CD19+, Thy1.2+ and CD11b+ cells were used as reference cell types in our assay. Eighty thousand cells from each type were washed in ice cold PBS prior to the assay. Libraries were single-end sequenced on a NexSeq500. The data was mapped to mm10 using and Tag directories with reads mapped to the mitochondrial chromosome filtered out and UCSC BedGraph files normalized to 10M total mapped reads were created using the HOMER platform ATAC-seq peaks were identified using findPeaks.pl in HOMER. RNA-Seq: Briefly, for T cell conditions primary leukemic ProB cells from mouse transheterozygote for Ebf1 +/- Pax5+/- (TH-LN377 & 619) was transduced either with ICN1-pMIG or pMIG retrovirus and were cocultured on OP9 for 14 days. CD19+ (from pMIG) or Thy1.2+ (from ICN1-pMIG) cells were sorted. For invitro myeloid differentiation experiment cells (TH-LN381 and 619) were transduced with pMIG or C/EBPα-ER-pMIG. After 5 days CD19+11b- (from pMIG) and CD19-CD11b+ (C/EBPα-ER-pMIG ) cells were sorted. For T cell kinetics experiment primary leukemic ProB cells (TH-LN683) was cocultured either on OP9 or OP9-DL1, CD19+Thy1.2+ (Day6) and CD19-Thy1.2+ (Day 14) cells were sorted. For myeloid kinetics experiment TH-LN381 cells were transduced with pMIG or C/EBPα-ER-pMIG and CD19+CD11b- (Day 1), CD19+CD11b+ (Day 2), CD19-CD11b+ (Day 5) were sorted. Lineage-KIT+Sca1+ (LSK) cells from Wt mouse were cultured either on B or T or Myeloid conditions and the CD19+, Thy1.2+ and CD11b+ cells were sorted and used as reference cell types in our assay. RNA were extracted with Qiagen RNaeasy Micro Kit. Librarys were constructed using Nugen's Ovation Ultralow Library systems and were subsequently for 76 cycles of NextSeq500 sequencing generating 20-30 million reads/sample. Data analysis was performed by aligned to mouse reference genome (mm10 /GRCm38) and analysed using the HOMER platform.
 
Contributor(s) Somasundaram R, Åhsberg J, Okuyama K, Ungerbäck J, Lilljebjörn H, Fioretos T, Strid T
Citation(s) 27913602
Submission date Nov 29, 2016
Last update date May 15, 2019
Contact name Rajesh Somasundaram
E-mail(s) rajesh.somasundaram19@gmail.com
Phone 0046708890787
Organization name Linkoping University
Department Microbiology and Molecular Medicine
Lab Lab 1, Floor- 13 Dept of Clinical and Experimental Medicine (IKE)
Street address Dept of Clinical and Experimental Medicine (IKE)
City Linkoping
ZIP/Postal code SE-58185
Country Sweden
 
Platforms (1)
GPL19057 Illumina NextSeq 500 (Mus musculus)
Samples (85)
GSM2410011 LN-381-CD11b+-CEBPa-transduced [ATAC-seq-TH-LN381-CEBPa-CD11b+_1]
GSM2410012 LN-381-CD11b+-CEBPa-transduced [ATAC-seq-TH-LN381-CEBPa-CD11b+_2]
GSM2410013 LN-381-CD19+-pMiG-transduced [ATAC-seq-TH-LN381-pMiG-CD19+_1]
Relations
BioProject PRJNA355290
SRA SRP094060

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE90655_Annotation-Cd11b-conversion-and-LSK-CD11b-on-CEBPa-peaks.txt.gz 2.8 Mb (ftp)(http) TXT
GSE90655_Annotation-Cd11b-conversion-and-LSK-CD11b-on-EBF1-peaks.txt.gz 861.9 Kb (ftp)(http) TXT
GSE90655_Annotation-Cd11b-conversion-and-LSK-CD11b-on-PAX5-peaks.txt.gz 600.8 Kb (ftp)(http) TXT
GSE90655_Annotation-M-cond-on-CEBPa-peaks-161012.txt.gz 2.8 Mb (ftp)(http) TXT
GSE90655_Annotation-M-cond-on-EBF1-peaks-161012.txt.gz 854.1 Kb (ftp)(http) TXT
GSE90655_Annotation-M-cond-on-PAX5-peaks-161012.txt.gz 592.5 Kb (ftp)(http) TXT
GSE90655_Annotation-M-conversion-on-merge-LSK_B-LSK_M-Top20K-peaks.txt.gz 2.6 Mb (ftp)(http) TXT
GSE90655_Annotation-T-Kinetic-on-EBF1-peaks.txt.gz 959.4 Kb (ftp)(http) TXT
GSE90655_Annotation-T-Kinetic-on-GATA3-peaks.txt.gz 546.5 Kb (ftp)(http) TXT
GSE90655_Annotation-T-Kinetic-on-PAX5-peaks.txt.gz 669.3 Kb (ftp)(http) TXT
GSE90655_Annotation-T-Kinetic-on-TCF1-peaks.txt.gz 2.8 Mb (ftp)(http) TXT
GSE90655_Annotation-T-conversion-on-merge-LSK_B-LSK_T-Top20K-peaks.txt.gz 2.7 Mb (ftp)(http) TXT
GSE90655_Annotation-TH-LSK-diff-on-CEBPa-peaks.txt.gz 3.0 Mb (ftp)(http) TXT
GSE90655_Annotation-TH-LSK-diff-on-EBF1-peaks.txt.gz 969.7 Kb (ftp)(http) TXT
GSE90655_Annotation-TH-LSK-diff-on-GATA3-peaks.txt.gz 546.1 Kb (ftp)(http) TXT
GSE90655_Annotation-TH-LSK-diff-on-PAX5-peaks.txt.gz 677.1 Kb (ftp)(http) TXT
GSE90655_Annotation-Thy-conversion-and-LSK-Thy-on-EBF1-peaks.txt.gz 868.9 Kb (ftp)(http) TXT
GSE90655_Annotation-Thy-conversion-and-LSK-Thy-on-GATA3-peaks.txt.gz 510.1 Kb (ftp)(http) TXT
GSE90655_Annotation-Thy-conversion-and-LSK-Thy-on-PAX5-peaks.txt.gz 607.4 Kb (ftp)(http) TXT
GSE90655_Annotation-WT-TH-LSK-Thy-LSK-Cd11b-on-CEBPa-peaks.txt.gz 3.1 Mb (ftp)(http) TXT
GSE90655_Annotation-WT-TH-LSK-Thy-LSK-Cd11b-on-EBF1-peaks.txt.gz 1015.2 Kb (ftp)(http) TXT
GSE90655_Annotation-WT-TH-LSK-Thy-LSK-Cd11b-on-GATA3.txt.gz 566.1 Kb (ftp)(http) TXT
GSE90655_Annotation-WT-TH-LSK-Thy-LSK-Cd11b-on-PAX5-peaks.txt.gz 709.8 Kb (ftp)(http) TXT
GSE90655_RNA-seq-50-norm-tags-count-exons-condenseGenes-M-Kinetic.txt.gz 408.4 Kb (ftp)(http) TXT
GSE90655_RNA-seq-50-norm-tags-count-exons-condenseGenes-M-diff.txt.gz 493.6 Kb (ftp)(http) TXT
GSE90655_RNA-seq-50-norm-tags-count-exons-condenseGenes-T-Kinetic.txt.gz 409.9 Kb (ftp)(http) TXT
GSE90655_RNA-seq-50-norm-tags-count-exons-condenseGenes-T-diff-LN-RNA-and-LSK-T.txt.gz 482.5 Kb (ftp)(http) TXT
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