Pluripotent Reprogramming of Human AML Resets Leukemic Behavior and Models Therapeutic Targeting of Subclones
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA353502 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Understanding the contribution of abnormal genetic and epigenetic programs to acute myeloid leukemia (AML) is necessary for the integrated design of targeted therapies. To investigate this, we determined the effect of epigenetic reprogramming on leukemic behavior by generating induced pluripotent stem cells (iPSCs) from AML patient samples harboring MLL rearrangements. AML-derived iPSCs (AML-iPSCs) retained leukemic mutations, but reset leukemic DNA methylation/gene expression patterns and lacked leukemic potential. However, when differentiated into hematopoietic cells, AML-iPSCs reacquired the ability to give rise to leukemia in vivo and reestablished leukemic methylation/gene expression patterns, including an aberrant MLL signature, indicating that epigenetic reprogramming was insufficient to eliminate leukemic behavior. In one case, we identified distinct AML-iPSC KRAS mutant and wildtype subclones that demonstrated differential growth properties and therapeutic susceptibilities, predicting KRAS wildtype clonal relapse due to increased cytarabine resistance. Increased cytarabine resistance was further observed in a cohort of KRAS wildtype MLL-rearranged AML samples, demonstrating the utility of AML-iPSCs in predicting subclonal relapse and facilitating clonal targeting in AML. This SuperSeries is composed of the SubSeries listed below.
2016-11-14 | GSE89778 | GEO
Project description:Understanding the contribution of abnormal genetic and epigenetic programs to acute myeloid leukemia (AML) is necessary for the integrated design of targeted therapies. To investigate this, we determined the effect of epigenetic reprogramming on leukemic behavior by generating induced pluripotent stem cells (iPSCs) from AML patient samples harboring MLL rearrangements. AML-derived iPSCs (AML-iPSCs) retained leukemic mutations, but reset leukemic DNA methylation/gene expression patterns and lacked leukemic potential. However, when differentiated into hematopoietic cells, AML-iPSCs reacquired the ability to give rise to leukemia in vivo and reestablished leukemic methylation/gene expression patterns, including an aberrant MLL signature, indicating that epigenetic reprogramming was insufficient to eliminate leukemic behavior. In one case, we identified distinct AML-iPSC KRAS mutant and wildtype subclones that demonstrated differential growth properties and therapeutic susceptibilities, predicting KRAS wildtype clonal relapse due to increased cytarabine resistance. Increased cytarabine resistance was further observed in a cohort of KRAS wildtype MLL-rearranged AML samples, demonstrating the utility of AML-iPSCs in predicting subclonal relapse and facilitating clonal targeting in AML.
2016-11-14 | GSE89776 | GEO
Project description:Understanding the contribution of abnormal genetic and epigenetic programs to acute myeloid leukemia (AML) is necessary for the integrated design of targeted therapies. To investigate this, we determined the effect of epigenetic reprogramming on leukemic behavior by generating induced pluripotent stem cells (iPSCs) from AML patient samples harboring MLL rearrangements. AML-derived iPSCs (AML-iPSCs) retained leukemic mutations, but reset leukemic DNA methylation/gene expression patterns and lacked leukemic potential. However, when differentiated into hematopoietic cells, AML-iPSCs reacquired the ability to give rise to leukemia in vivo and reestablished leukemic methylation/gene expression patterns, including an aberrant MLL signature, indicating that epigenetic reprogramming was insufficient to eliminate leukemic behavior. In one case, we identified distinct AML-iPSC KRAS mutant and wildtype subclones that demonstrated differential growth properties and therapeutic susceptibilities, predicting KRAS wildtype clonal relapse due to increased cytarabine resistance. Increased cytarabine resistance was further observed in a cohort of KRAS wildtype MLL-rearranged AML samples, demonstrating the utility of AML-iPSCs in predicting subclonal relapse and facilitating clonal targeting in AML.
2016-11-14 | GSE89777 | GEO
Project description:Intra-tumour heterogeneity caused by clonal evolution is a major problem in cancer treatment stratification. To address this problem, we performed label-free quantitative proteomics on primary acute myeloid leukemia (AML) samples. We identified 50 leukemia-enriched plasma membrane (PM) proteins enabling the prospective isolation of genetically distinct subclones from individual AML patients. Subclones differed in their regulatory phenotype, drug sensitivity, growth and engraftment behavior, as determined by RNA sequencing, DNaseI hypersensitive site mapping, transcription factor occupancy analysis, in vitro culture and xenograft transplantation. Finally, we show that these markers can be used to identify and longitudinally track distinct leukemic clones in patients in routine diagnostics. Our study describes a strategy for a major improvement in stratifying cancer diagnosis and treatment.
2018-07-26 | GSE117667 | GEO
Project description:The tracking of leukemic clones in acute myeloid leukemic promisses deeper insights into disease development and therapeutic options. We therefore established a fluorescent genetic barcoding (FGB) labeling approach that allows for flow cytomtric tracking of color-coded clones in vitro and in vivo. In Hoxa9 and Meis1 (H9M) dependent murine AML, we tracked the growth behavior of 24 clones in parallel and enriched for pre-leukemic clones as well as their de novo expanded counterparts and stably expanded clones from leukemic mice by fluorescence-activated cell sorting. These samples were subjected toRNA sequencing for the assessment of transcriptional changes underlying clonal maintenance and expansion.
2022-12-28 | GSE198371 | GEO
Project description:Pluripotent Reprogramming of Human AML Resets Leukemic Behavior and Models Therapeutic Targeting of Subclones [methylation]
| PRJNA353556 | ENA
Project description:Pluripotent Reprogramming of Human AML Resets Leukemic Behavior and Models Therapeutic Targeting of Subclones [RNA-seq]
| PRJNA353508 | ENA
Project description:Genetic heterogeneity though common in tumors has been rarely documented in cell lines. To examine how often B-lymphoma cell lines are comprised of subclones, we performed immunoglobulin (Ig) heavy chain hypermutation analysis. Revealing that subclones are not rare in B-cell lymphoma cell lines, 6/49 Ig hypermutated cell lines (12%) consisted of subclones with individual Ig mutations. Subclones were also identified in 2/284 leukemia/lymphoma cell lines exhibiting bimodal CD marker expression. We successfully isolated 10 subclones from four cell lines HG3, SU-DHL-5, TMD-8, U-2932). Whole exome sequencing was performed to molecularly characterize these subclones. We in detail describe the clonal structure of cell line HG3, derived from chronic lymphocytic leukemia. HG3 consists of three lineages each bearing clone-specific aberrations, gene expression and DNA methylation patterns. While donor patient leukemic cells were CD5+ , two of three HG3 subclones had independently lost this marker. CD5 on HG3 cells was regulated by epigenetic/transcriptional mechanisms rather than by alternative splicing as reported hitherto. In conclusion, we show that the presence of subclones in cell lines carrying individual mutations and characterized by sets of differentially expressed genes is not uncommon. We show also that these subclones can be useful isogenic models for regulatory and functional studies.
2016-09-30 | E-MTAB-4955 | biostudies-arrayexpress
Project description:Genetic heterogeneity though common in tumors has been rarely documented in cell lines. To examine how often B-lymphoma cell lines are comprised of subclones, we performed immunoglobulin (Ig) heavy chain hypermutation analysis. Revealing that subclones are not rare in B-cell lymphoma cell lines, 6/49 Ig hypermutated cell lines (12%) consisted of subclones with individual Ig mutations. Subclones were also identified in 2/284 leukemia/lymphoma cell lines exhibiting bimodal CD marker expression. We successfully isolated 10 subclones from four cell lines HG3, SU-DHL-5, TMD-8, U-2932). Whole exome sequencing was performed to molecularly characterize these subclones. We in detail describe the clonal structure of cell line HG3, derived from chronic lymphocytic leukemia. HG3 consists of three lineages each bearing clone-specific aberrations, gene expression and DNA methylation patterns. While donor patient leukemic cells were CD5+, two of three HG3 subclones had independently lost this marker. CD5 on HG3 cells was regulated by epigenetic/transcriptional mechanisms rather than by alternative splicing as reported hitherto. In conclusion, we show that the presence of subclones in cell lines carrying individual mutations and characterized by sets of differentially expressed genes is not uncommon. We show also that these subclones can be useful isogenic models for regulatory and functional studies.
2016-09-30 | E-MTAB-4956 | biostudies-arrayexpress
Project description:The parasite Plasmodium falciparum is responsible for severe malaria, which remains a major cause of death, particularly in sub-Saharan Africa. The reference strain NF54 (or its subclone 3D7) is commonly used for controlled human malaria infection (CHMI), but recently strains with a different geographic and genomic background have become available for CHMI, including 7G8, which was subcloned from the Brazilian isolate IMTM22 in 1984 (Burkot TR et al. 1984. Infectivity to mosquitoes of Plasmodium falciparum clones grown in vitro from the same isolate. Trans R Soc Trop Med Hyg 78 (3):339-41. doi: 10.1016/0035-9203(84)90114-7). In contrast to NF54, in which var gene expression resets after mosquito transmission, 7G8 shows a partial reset with retention of the C-type var gene PF7G8_040025600 in the human host. The three subclones A1G9 (almost exclusive var2csa expression, control), A2E10, and A2G2 (both predominantly expressing var gene PF7G8_040025600) recently obtained by limited dilution from the Sanaria 7G8 parasite working cell bank (Lot: SAN03-021214 dated 20. February 2014) were selected for gDNA sequencing to test whether parasite subclones expressing PF7G8_040025600 differ in their genomic background. 150 mL of P. falciparum cell culture with >10% parasitemia was harvested and gDNA isolation was performed using the MasterPure™ Complete DNA Purification Kit (Lucigen). The gDNA samples were tested for degradation and RNA contamination on an agarose gel and quantified using the Qubit™ dsDNA BR Assay Kit (ThermoFischer). DNA-seq was performed at BGI Genomics (Shenzhen, China) on the DNBseq platform to generate 150 bp paired-end sequencing reads.
2022-09-22 | E-MTAB-12158 | biostudies-arrayexpress