Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Patient-derived iPSCs faithfully represent the genetic diversity and cellular architecture of human acute myeloid leukemia

ABSTRACT: The reprogramming of human acute myeloid leukemia (AML) cells into induced pluripotent stem cell (iPSC) lines could provide new faithful genetic models of AML, but is currently hindered by low success rates and uncertainty about whether iPSC-derived cells resemble their primary counterparts. Here we developed a reprogramming method tailored to cancer cells, with which we generated iPSCs from 15 patients representing all major genetic groups of AML. These AML-iPSCs retain genetic fidelity and produce transplantable hematopoietic cells with hallmark phenotypic leukemic features. Critically, single-cell transcriptomics reveal that, upon xenotransplantation, iPSC-derived leukemias faithfully mimic the primary patient-matched xenografts. Transplantation of iPSC-derived leukemias capturing a clone and subclone from the same patient allowed us to isolate the contribution of a FLT3-ITD mutation to the AML phenotype. The results and resources reported here can transform basic and preclinical cancer research of AML and other human cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE210889 | GEO | 2023/04/18

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Pluripotent Reprogramming of Human AML Resets Leukemic Behavior and Models Therapeutic Targeting of Subclones [methylation]

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

Pluripotent Reprogramming of Human AML Resets Leukemic Behavior and Models Therapeutic Targeting of Subclones

2016-11-14 | GSE89778 | GEO

Pluripotent Reprogramming of Human AML Resets Leukemic Behavior and Models Therapeutic Targeting of Subclones [RNA-seq]

2016-11-14 | GSE89777 | GEO

mRNA expression data from iPSCs, ntESCs and iPSC-nt-ESCs

Project description:We generated three kinds of genetically identical mouse reprogrammed cells: induced pluripotent stem cells (iPSCs), nuclear transfer embryonic stem cells (ntESCs) and iPSC-nt-ESCs that are established after successively reprogramming of iPSCs by nuclear transfer (NT). NtESCs show better developmental potential than iPSCs, whereas iPSC-nt-ESCs display worse developmental potential than iPSCs. We used microarrays to distinguish the gene expression differences among three pluriptoent stem cells and identified that imprinted genes had a similar expression pattern in iPSCs and iPSC-nt-ESCs. We sought to obtain genetic identical pluripotent stem cell lines in order to minimize genetic variations among different reprogrammed cells. To that end, we established a genetically homogenous secondary reprogramming system, in which mouse embryonic fibroblasts (MEFs) carrying doxycycline (dox)-inducible lentiviruses expressing Oct4, Sox2, Klf4 and c-Myc were isolated and used as donors for different reprogramming experiments. We generated iPSCs after plating MEFs in the presence of dox in ES culture conditions, and then derived ntESCs after transplantation of the nucleus from the same MEFs into enucleated oocyte. Furthermore, we successively reprogrammed iPSCs by means of NT and established a set of nt-iPSC lines. Pluripotent stem cells generated from different reprogramming strategies were for RNA extraction and hybridization on Affymetrix microarrays.

2011-05-31 | E-GEOD-24705 | biostudies-arrayexpress

RNA-seq of CN, CN/AML, and CN/AML BAALC KO iPSCs-derived HSPCs

Project description:Severe congenital neutropenia (CN) is a pre-leukemia syndrome that, in the majority of patients, is caused by heterogeneous ELANE mutations encoding neutrophil elastase (NE). To study leukemogenesis associated with CN we generated CN and CN/AML patient-specific induced pluripotent stem cells (iPSCs). Additional mutations in leukemia-relevant genes, CSF3R and RUNX1, were introduced using CRISPR/Cas9 gene-editing. Consequently, we performed in vitro embryoid body (EB)-based hematopoietic and myeloid differentiation of generated iPSC lines. On day 14-17 of EB-based differentiation, iPSC-derived CD45+CD34+ cells were harvested and mRNA was isolated using RNeasy Mini- or Micro Kit (Qiagen). Sequencing libraries were prepared using the TruSeq RNA Sample Prep Kit (Illumina). Poly (A) selected single-read and pair-read sequencing libraries were sequenced on the Illumina platform in order to compare the transcriptomes of CN and CN/AML iPSCs-derived HSPCs from 2 CN/AML patients. Next, we identified that BAALC knockout resulted in a dramatic induction of granulocytic differentiation and a significant reduction in proliferation of CN/AML iPSC-derived HSPCs. To identify BAALC-dependent leukemia-associated gene expression, we compared the transcriptomes of CN/AML iPSCs before and after BAALC KO using a similar approach described above for CN and CN/AML iPSCs-derived HSPCs.

2021-03-08 | E-MTAB-10162 | biostudies-arrayexpress

Reprogramming-associated aberrant DNA methylation determines hematopoietic differentiation capacity of human induced pluripotent stem cells [iPS_derived_erythroiblasts]

Project description:The variation among induced pluripotent stem cells (iPSCs) in their differentiation capacity to specific lineages is frequently attributed to somatic memory. In this study, we compared hematopoietic differentiation capacity of 35 human iPSC lines derived from four different tissues and four embryonic stem cell lines. The analysis revealed that hematopoietic commitment capacity (PSCs to hematopoietic precursors) is correlated with the expression level of the IGF2 gene independent of the iPSC origins. In contrast, maturation capacity (hematopoietic precursors to mature blood) is affected by iPSC origin; blood-derived iPSCs showed the highest capacity. However, some fibroblast-derived iPSCs showed higher capacity than blood-derived clones. Tracking of DNA methylation changes during reprogramming reveals that maturation capacity is highly associated with aberrant DNA methylation acquired during reprogramming, rather than the types of iPSC origins. These data demonstrated that variations in the hematopoietic differentiation capacity of iPSCs are not attributable to somatic memories of their origins. iPSC-derived erythroblasts (n = 1)

2016-06-29 | E-GEOD-60922 | biostudies-arrayexpress

Reprogramming-associated aberrant DNA methylation determines hematopoietic differentiation capacity of human induced pluripotent stem cells [Erythroid_lines]

2016-06-29 | E-GEOD-75095 | biostudies-arrayexpress

GM-CSF-transduced proliferating myeloid cells represent cell cycle related gene signature

Project description:We previously established a method to generate myeloid lineage cells with proliferation capacity from induced pluripotent stem cells (iPSCs) (Zhang R. Cancer Immunol Res. 3: 668, 2015). In this study, we generated the GM-CSF-producing cells by genetic engineering of mouse iPSC-derived proliferation myeloid cells (iPSC-pMCs). Gene expression profiles revealed GM-CSF-transduced iPSC-pMCs (GM-pMCs) generated from C57BL/6 mice and 129Sv mice shared 180 up-regulated genes and 236 down-regulated genes compared with their corresponding iPSC-pMCs. Gene ontology analysis showed that the up-regulated gene signature shared by C57BL/6 GM-pMCs and 129Sv GM-pMCs was enriched for transcripts associate with cell cycle, cell cycle process, mitotic cell cycle and regulation of mitotic cell cycle.

2020-08-31 | GSE136993 | GEO

Reprogramming-associated aberrant DNA methylation determines hematopoietic differentiation capacity of human induced pluripotent stem cells [parental_lines_expression]

2016-06-29 | E-GEOD-73629 | biostudies-arrayexpress

Reprogramming-associated aberrant DNA methylation determines hematopoietic differentiation capacity of human induced pluripotent stem cells [iPSC_ESC_lines]

2016-06-29 | E-GEOD-75096 | biostudies-arrayexpress