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

Coline Gaillard, Taku A. Tokuyasu, Galit Rosen, Jason Sotzen, Adeline Vitaliano-Prunier, Ritu Roy, Emmanuelle Passegué, Hugues De Thé, Maria Figueroa, Scott C. Kogan

Research output: Contribution to journalArticle

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Abstract

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 young preleukemic animals, carried out microarray and methylation profiling analyses, and compared the results from the two groups of animals. Surprisingly, in the absence of secondary lesions, PML/RARA had an overall limited impact on both the transcriptome and methylome. Of interest, we did identify down-regulation of secondary and tertiary granule genes as the first step engaging the myeloid maturation block. Although initially not sufficient to arrest terminal granulopoiesis in vivo, such alterations set the stage for the later, complete differentiation block seen in leukemia. Further, gene set enrichment analysis revealed that PML/RARA promyelocytes exhibit a subtle increase in expression of cell cycle genes, and we show that this leads to both increased proliferation of these cells and expansion of the promyelocyte compartment. Importantly, this proliferation signature was absent from the poorly leukemogenic p50/RARA fusion model, implying a critical role for PML in the altered cell-cycle kinetics and ability to initiate leukemia. Thus, our findings challenge the predominant model in the field and we propose that PML/RARA initiates leukemia by subtly shifting cell fate decisions within the promyelocyte compartment.

Original languageEnglish (US)
Pages (from-to)1064-1075
Number of pages12
JournalHaematologica
Volume100
Issue number8
DOIs
StatePublished - Aug 5 2015
Externally publishedYes

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Granulocyte Precursor Cells
Methylation
Leukemia
cdc Genes
Acute Promyelocytic Leukemia
Transcriptome
Genes
Cell Cycle
Down-Regulation
Bone Marrow
Cell Proliferation
Pathology
Population
Neoplasms
Proteins

ASJC Scopus subject areas

  • Hematology

Cite this

Gaillard, C., Tokuyasu, T. A., Rosen, G., Sotzen, J., Vitaliano-Prunier, A., Roy, R., ... Kogan, S. C. (2015). Transcription and methylation analyses of preleukemic promyelocytes indicate a dual role for PML/RARA in leukemia initiation. Haematologica, 100(8), 1064-1075. https://doi.org/10.3324/haematol.2014.123018

Transcription and methylation analyses of preleukemic promyelocytes indicate a dual role for PML/RARA in leukemia initiation. / Gaillard, Coline; Tokuyasu, Taku A.; Rosen, Galit; Sotzen, Jason; Vitaliano-Prunier, Adeline; Roy, Ritu; Passegué, Emmanuelle; De Thé, Hugues; Figueroa, Maria; Kogan, Scott C.

In: Haematologica, Vol. 100, No. 8, 05.08.2015, p. 1064-1075.

Research output: Contribution to journalArticle

Gaillard, C, Tokuyasu, TA, Rosen, G, Sotzen, J, Vitaliano-Prunier, A, Roy, R, Passegué, E, De Thé, H, Figueroa, M & Kogan, SC 2015, 'Transcription and methylation analyses of preleukemic promyelocytes indicate a dual role for PML/RARA in leukemia initiation', Haematologica, vol. 100, no. 8, pp. 1064-1075. https://doi.org/10.3324/haematol.2014.123018
Gaillard, Coline ; Tokuyasu, Taku A. ; Rosen, Galit ; Sotzen, Jason ; Vitaliano-Prunier, Adeline ; Roy, Ritu ; Passegué, Emmanuelle ; De Thé, Hugues ; Figueroa, Maria ; Kogan, Scott C. / Transcription and methylation analyses of preleukemic promyelocytes indicate a dual role for PML/RARA in leukemia initiation. In: Haematologica. 2015 ; Vol. 100, No. 8. pp. 1064-1075.
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AU - Sotzen, Jason

AU - Vitaliano-Prunier, Adeline

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