Unknown,Transcriptomics,Genomics,Proteomics

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The ability of PML/RARα to initiate leukemia is associated with markedly increased proliferation of promyelocytes despite minor changes in the transcriptome and epigenome.


ABSTRACT: Acute Promyelocytic Leukemia is characterized by the accumulation in the blood and bone marrow of promyelocytes. The PML/RARα fusion protein is identified as the primary abnormality implicated in the pathology, and is believed to prevent transcription of genes necessary for normal myeloid development and differentiation. Identifying its targets is critical to comprehend the road to pathogenesis. To understand how PML/RARα, in the absence of secondary lesions, alters gene expression, DNA methylation and proliferation we used a novel experimental and sorting strategy to study normal versus preleukemic promyelocytes in vivo. Expression and methylation profiling analyses were performed on highly purified samples. Surprisingly, despite its ability to initiate leukemia, PML/RARα had overall minor effects on both the transcriptome and epigenome. Important regulators of the myeloid maturation program were not altered but, remarkably, PML/RARα promyelocytes showed strong downregulation of secondary and tertiary granule genes. Subtle changes were also observed on the DNA methylation profile, with PML/RARα predominantly mediating hypomethylation. We performed intersection studies between altered loci and previously described PML/RARα binding sites but found little overlap. Importantly, we show for the first time that PML/RARα on its own increases proliferation, and that this increased proliferation correlates with the ability to initiate leukemia. DNA methylation profiling in CD34(+) early promyelocytes and CD34(-) late promyelocytes cells from PML-RARa transgenic mice vs. control mice.

ORGANISM(S): Mus musculus

SUBMITTER: Maria Figueroa 

PROVIDER: E-GEOD-54038 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Transcription and methylation analyses of preleukemic promyelocytes indicate a dual role for PML/RARA in leukemia initiation.

Gaillard Coline C   Tokuyasu Taku A TA   Rosen Galit G   Sotzen Jason J   Vitaliano-Prunier Adeline A   Roy Ritu R   Passegué Emmanuelle E   de Thé Hugues H   Figueroa Maria E ME   Kogan Scott C SC  

Haematologica 20150618 8


Acute promyelocytic leukemia is an aggressive malignancy characterized by the accumulation of promyelocytes in the bone marrow. PML/RARA is the primary abnormality implicated in this pathology, but the mechanisms by which this chimeric fusion protein initiates disease are incompletely understood. Identifying PML/RARA targets in vivo is critical for comprehending the road to pathogenesis. Utilizing a novel sorting strategy, we isolated highly purified promyelocyte populations from normal and youn  ...[more]

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