Deletion of the Hoxa Cluster in MLL-AF9 Is Incompatible with Leukemia Maintenance: RNAseq-based Quantitative Analysis of Wild Type and Hoxa-del Transcriptomes
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA450411 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7010870_1.fastq.gz | Fastqsanger.gz | |||
| SRR7010870_2.fastq.gz | Fastqsanger.gz | |||
| SRR7010880_1.fastq.gz | Fastqsanger.gz | |||
| SRR7010880_2.fastq.gz | Fastqsanger.gz | |||
| SRR7010871_1.fastq.gz | Fastqsanger.gz |
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Project description:A t(9;11)(p22;q23) translocation produces the MLL-AF9 fusion protein, which is found in up to 25% of de novo AML cases in children. Despite major advances, obtaining a comprehensive under-standing of context-dependent MLL-AF9-mediated gene programs during early hematopoiesis is challenging. Here, we generated a human inducible pluripotent stem cell (hiPSC) model with a doxycycline dose-dependent MLL-AF9 expression. We exploited MLL-AF9 expression as an onco-genic hit to uncover epigenetic and transcriptomic effects on iPSC-derived hematopoietic develop-ment and the transformation into (pre-)leukemic states. In doing so, we observed a disruption in early myelomonocytic development. Accordingly, we identified gene profiles that were consistent with primary MLL-AF9 AML and uncovered high-confidence MLL-AF9-associated core genes that are faithfully represented in primary MLL-AF9 AML, including known and presently unknown factors. Using single-cell RNA-sequencing, we identified an increase of CD34 expressing early hematopoietic progenitor-like cell states as well as granulocyte-monocyte progenitor-like cells upon MLL-AF9 activation. Our system allows for careful chemically controlled and stepwise in vitro hiPSC-derived differentiation under serum-free and feeder-free conditions. For a disease that cur-rently lacks effective precision medicine, our system provides a novel entry-point into exploring po-tential novel targets for personalized therapeutic strategies.
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Project description:To explore oncogene addiction programs in a genetically defined leukemia context we developed an AML mouse model driven by a conditional MLL-AF9 allele together with oncogenic Ras, which enabled us to examine the consequences of MLL-AF9 inhibition in established disease. In order to produce a tightly regulated system that was easy to monitor, we constructed two retroviral vectors containing dsRed-linked MLL-AF9 under control of a tetracycline response element promoter, and KrasG12D or NrasG12D linked to the “Tet-off” tet-transactivator, which activates TRE expression in a doxycycline repressible manner. Leukemias were generated by retroviral cotransduction of both vectors into hematopoietic stem and progenitor cells, which were transplanted into syngeneic mice. Cells harboring both constructs induced aggressive myelomonocytic leukemia. Five independent primary leukemia cell lines were established from bone marrow of terminal mice. Treatment of these lines with doxycycline rapidly turned off MLL-AF9 expression, and induced terminal myeloid differentiation and complete disease remission in vivo. To identify molecular mechanisms underlying addiction to MLL-AF9, we analyzed global gene expression changes following doxycycline-induced suppression of MLL-AF9. Independent primary acute myeloid leukemia lines induced by cotransduction of Tet-off MLL-AF9 together with either KrasG12D or NrasG12D were grown in culture and treated with doxycycline for 6 days to inactivate MLL-AF9 expression. In addition, primary acute myeloid leukemia lines with constitutive MLL-AF9 and KrasG12D were included to control for the effects of doxycycline. Untreated and treated cells were harvested for RNA extraction and hybridization to Affymetrix arrays.
2011-08-04 | E-GEOD-30746 | biostudies-arrayexpress
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