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| Status |
Public on Sep 01, 2017 |
| Title |
Dnmt3a haploinsufficiency transforms Flt3-ITD myeloproliferative disease into a rapid, spontaneous, and fully-penetrant acute myeloid leukemia |
| Organisms |
Homo sapiens; Mus musculus |
| Experiment type |
Methylation profiling by high throughput sequencing
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| Summary |
Cytogenetically normal acute myeloid leukemia (CN-AML) represents nearly 50% of human acute myeloid leukemia (AML) cases with a 5-year overall survival of approximately 30%. In CN-AML with poorer prognosis, mutations in the de novo DNA methyltransferase (DNMT3A) and the FMS-like tyrosine kinase 3 (Flt3) commonly co-occur (1-3). We demonstrate that mice with Flt3-internal-tandem duplication (Flt3ITD) and inducible deletion of Dnmt3a spontaneously develop a rapidly-lethal, completely-penetrant, and transplantable AML of normal karyotype. These murine AML retain a single Dnmt3a floxed allele, revealing the oncogenic potential of Dnmt3a haploinsufficiency. FLT3-ITD/DNMT3A-mutant primary human and murine AML demonstrate a similar pattern of global DNA methylation. In the murine model, rescuing DNMT3A expression was accompanied by DNA re-methylation and loss of clonogenic potential, suggesting that Dnmt3a-mutant oncogenic effects are reversible. Differentially methylated genomic regions were associated with changes in the expression of nearby genes. Moreover, dissection of the cellular architecture of the AML model using single-cell RNA-Seq, flow cytometry and colony assays identified clonogenic subpopulations that differentially express genes that are sensitive to the methylation of nearby genomic loci and varied in response to Dnmt3a levels. Thus, Dnmt3a haploinsufficiency transforms Flt3ITD myeloproliferative disease by modulating methylation-sensitive gene expression within a clonogenic AML subpopulation.
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| Overall design |
To identify the DNA methylation changes associated with Dnmt3a loss of function in human and murine Flt3-ITD and Dnmt3a-mutant AML.
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| Contributor(s) |
Meyer SE, Qin T, Muench DE, Masuda K, Venkatasubramanian M, Orr E, Paietta E, Tallman MS, Fernandez H, Melnick A, Le Beau MM, Kogan S, Salomonis N, Figueroa ME, Grimes HL |
| Citation(s) |
27016502 |
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| Submission date |
Jan 20, 2016 |
| Last update date |
May 15, 2019 |
| Contact name |
Maria E Figueroa |
| E-mail(s) |
mef162@miami.edu
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| Phone |
(305) 243-7333
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| Organization name |
University of Miami
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| Department |
Human Genetics
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| Lab |
Maira Figueroa
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| Street address |
1501 NW 10th Ave
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| City |
Miami |
| State/province |
FL |
| ZIP/Postal code |
33136 |
| Country |
USA |
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| Platforms (2) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
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| Samples (44)
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| GSM2042688 |
5286 Flt3ITD/ITD,DNMT3Amut |
| GSM2042689 |
6239 Flt3ITD/ITD,DNMT3Amut |
| GSM2042690 |
6374 Flt3ITD/ITD,DNMT3Amut |
| GSM2042691 |
7131 Flt3ITD/ITD,DNMT3Amut |
| GSM2042692 |
7411 Flt3ITD/ITD,DNMT3Amut |
| GSM2042693 |
14707 Flt3ITD/ITD,DNMT3Amut |
| GSM2042694 |
15492 Flt3ITD/ITD,DNMT3Amut |
| GSM2042695 |
19274 Flt3ITD/ITD,DNMT3Amut |
| GSM2042696 |
19694 Flt3ITD/ITD,DNMT3Amut |
| GSM2042697 |
20599 Flt3ITD/ITD,DNMT3Amut |
| GSM2042698 |
322 Flt3ITD/ITD,DNMT3Awt |
| GSM2042699 |
2179 Flt3ITD/ITD,DNMT3Awt |
| GSM2042700 |
2197 Flt3ITD/ITD,DNMT3Awt |
| GSM2042701 |
2230 Flt3ITD/ITD,DNMT3Awt |
| GSM2042702 |
2236 Flt3ITD/ITD,DNMT3Awt |
| GSM2042703 |
2248 Flt3ITD/ITD,DNMT3Awt |
| GSM2042704 |
2301 Flt3ITD/ITD,DNMT3Awt |
| GSM2042705 |
2327 Flt3ITD/ITD,DNMT3Awt |
| GSM2042706 |
5287 Flt3ITD/ITD,DNMT3Awt |
| GSM2042707 |
6237 Flt3ITD/ITD,DNMT3Awt |
| GSM2042708 |
6379 Flt3ITD/ITD,DNMT3Awt |
| GSM2042709 |
6463 Flt3ITD/ITD,DNMT3Awt |
| GSM2042710 |
7051 Flt3ITD/ITD,DNMT3Awt |
| GSM2042711 |
7052 Flt3ITD/ITD,DNMT3Awt |
| GSM2042713 |
7176 Flt3ITD/ITD,DNMT3Awt |
| GSM2042714 |
7421 Flt3ITD/ITD,DNMT3Awt |
| GSM2042723 |
8303 Flt3ITD/ITD,Dnmt3afl/- MxCre AML |
| GSM2042724 |
9301 Flt3ITD/ITD,Dnmt3afl/- MxCre AML |
| GSM2042725 |
9797 Flt3ITD/ITD,Dnmt3afl/- MxCre AML |
| GSM2042726 |
9796 Flt3ITD/ITD,Dnmt3afl/fl MPN |
| GSM2042727 |
9798 Flt3ITD/ITD,Dnmt3afl/fl MPN |
| GSM2042728 |
9927 Flt3ITD/ITD,Dnmt3afl/fl MPN |
| GSM2042729 |
9301_K_SP_WT_DNMT |
| GSM2042730 |
9797_K_SP_WT_DNMT |
| GSM2042731 |
9301_K_SP_MIEG3 |
| GSM2042732 |
9797_K_SP_MIEG3 |
| GSM2071673 |
45205 HSC |
| GSM2071674 |
45207 HSC |
| GSM2071675 |
45209 HSC |
| GSM2071676 |
45211 HSC |
| GSM2071677 |
45213 HSC |
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| Relations |
| BioProject |
PRJNA309321 |
| SRA |
SRP068671 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE77026_RAW.tar |
1.2 Gb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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