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Aberrant DNA methylation impacts HOX genes expression in bone marrow mesenchymal stromal cells of myelodysplastic syndromes and de novo acute myeloid leukemia

Cancer Gene Therapy volume 29, pages 1263–1275 (2022)Cite this article

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Abstract

DNA methylation, a major biological process regulating the transcription, contributes to the pathophysiology of hematologic malignancies, and hypomethylating agents are commonly used to treat myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML). In these diseases, bone marrow mesenchymal stromal cells (MSCs) play a key supportive role through the production of various signals and interactions. The DNA methylation status of MSCs, likely to reflect their functionality, might be relevant to understand their contribution to the pathophysiology of these diseases. Consequently, the aim of our study was to analyze the modifications of DNA methylation profiles of MSCs induced by MDS or AML. MSCs from MDS/AML patients were characterized via 5-methylcytosine quantification, gene expression profiles of key regulators of DNA methylation, identification of differentially methylated regions (DMRs) by methylome array, and quantification of DMR-coupled genes expression. MDS and AML-MSCs displayed global hypomethylation and under-expression of DNMT1 and UHRF1. Methylome analysis revealed aberrant methylation profiles in all MDS and in a subgroup of AML-MSCs. This aberrant methylation was preferentially found in the sequence of homeobox genes, especially from the HOX family (HOXA1, HOXA4, HOXA5, HOXA9, HOXA10, HOXA11, HOXB5, HOXC4, and HOXC6), and impacted on their expression. These results highlight modifications of DNA methylation in MDS/AML-MSCs, both at global and focal levels dysregulating the expression of HOX genes well known for their involvement in leukemogenesis. Such DNA methylation in MSCs could be the consequence of the malignant disease or could participate in its development through defective functionality or exosomal transfer of HOX transcription factors from MSCs to hematopoietic cells.

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Fig. 1: Both the proliferative and methylation landscapes are altered in pathological MSCs and AML-MSCs display a decreased proliferative capacity.
Fig. 2: DNA methylation-regulating enzymes are dysregulated in MDS and AML-MSCs.
Fig. 3: DNA methylation profiles in MDS and AML-MSCs.
Fig. 4: Graphical representation of DMRs distribution in MSCs subgroups.
Fig. 5: Homeobox genes expression is altered in different pathological conditions.
Fig. 6: Illustrative distribution of DMPs in differentially expressed homeobox genes (HOX genes family) associated with the aberrant methylation profiles.

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Acknowledgements

The authors acknowledge Philippe Rosset for collecting healthy donors’ samples, Sophie Hamard for the isolation of healthy donors’ MSCs, Lamya Haddaoui, and all the participants of the FILOthèque. This work was supported by the International Rotary Club of Blois and Sapins de l’Espoir Contre le Cancer, CANCEN, and AHB associations. The authors declare no competing financial interests.

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Author notes

  1. These authors contributed equally: Benjamin Roux, Frédéric Picou.

Authors and Affiliations

  1. CNRS EMR 7001 LNOx “Leukemic niche & redox metabolism”, Tours, France

    Benjamin Roux, Frédéric Picou, Christelle Debeissat, Myriam Koubi, Nathalie Gallay, Noémie Ravalet, Emmanuel Gyan, Jorge Domenech & Olivier Herault

  2. EA 7501 GICC, université de Tours, Tours, France

    Benjamin Roux, Frédéric Picou, Christelle Debeissat, Myriam Koubi, Nathalie Gallay, Noémie Ravalet, Emmanuel Gyan, Jorge Domenech & Olivier Herault

  3. CHU de Tours, Service d’Hématologie Biologique, Tours, France

    Benjamin Roux, Frédéric Picou, Christelle Debeissat, Nathalie Gallay, Noémie Ravalet, Jorge Domenech & Olivier Herault

  4. Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Hôpital Saint-Antoine, Service d’Hématologie Biologique, Paris, France

    Pierre Hirsch & François Delhommeau

  5. CHU de Nantes, Service d’Hématologie Biologique, CRCINA, Nantes, France

    Marie C. Béné

  6. FHU GOAL, Angers, France

    Marie C. Béné, Mathilde Hunault & Olivier Herault

  7. CH de Chartres, Chartres, France

    Michel Maigre

  8. CHU d’Angers, Service d’Hématologie, Angers, France

    Mathilde Hunault

  9. CHU de Rennes, Service de Génétique Moléculaire et Génomique, Rennes, France

    Jean Mosser & Amandine Etcheverry

  10. Cancéropôle Grand Ouest, Nantes, France

    Jean Mosser & Olivier Herault

  11. CHU de Tours, Service d’Hématologie et Thérapie Cellulaire, Tours, France

    Emmanuel Gyan

  12. CNRS GDR 3697 Micronit “Microenvironment of tumor niches”, Tours, France

    François Delhommeau & Olivier Herault

  13. OPALE Carnot Institute, The Organization for Partnerships in Leukemia, Hôpital Saint-Louis, Paris, France

    François Delhommeau & Olivier Herault

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Contributions

Conduction of experiments and acquisition of data: BR, FP, CD, MK, NG, PH, and AE; material support: MM, MH, EG, and JD; bioinformatics analysis: JM and FP; analysis and interpretation of data: OH, BR, FP, CD, MK, NG, PH, FD, EG, and JD; writing of the article: BR, FP, and OH; editing of the article: MCB; conception, development of methodology, experiment design and performance, study supervision: OH. All the authors reviewed the paper.

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Correspondence to Olivier Herault.

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Roux, B., Picou, F., Debeissat, C. et al. Aberrant DNA methylation impacts HOX genes expression in bone marrow mesenchymal stromal cells of myelodysplastic syndromes and de novo acute myeloid leukemia. Cancer Gene Ther 29, 1263–1275 (2022). https://doi.org/10.1038/s41417-022-00441-w

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