Abstract 2408: Epigenomic characterization of MSC from myeloid malignancies

• Published in: Cancer research (Chicago, Ill.) Ill.), 2017-07, Vol.77 (13_Supplement), p.2408-2408
• Main Authors: Rodríguez-Paredes, Manuel, Geyh, Stefanie, Gazorpak, Mahshid, Gutekunst, Julian, Bormann, Felix, Haas, Rainer, Schröder, Thomas, Lyko, Frank
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2017-2408

Ineffective hematopoiesis is a hallmark of myeloid malignancies such as Myelodysplastic Syndromes (MDS) or Acute Myeloid Leukemia (AML). Our previous research has shown that mesenchymal stromal cells (MSC), one of the main cellular regulatory components of the bone marrow niche and essential for the differentiation of new blood cells from Hematopoietic Stem Cells (HSC), are molecularly and functionally impaired in MDS and AML patients. More specifically, these cells display reduced proliferative and differentiation capacities, an increased cellular senescence, or the altered expression of key hematopoietic factors, defects that can provide an explanation for the cytopenia associated with these diseases. But most interestingly, we have also discovered that MDS- and AML-derived MSC present aberrant methylomes. Our data, based on 450k DNA methylation microarrays, show that these abnormalities are shared by the MSC from both malignancies and affect key transcription factors like TBX15, PITX2 or HOXB6, formerly linked to differentiation and development. This results can account for some of the defects observed in the disease-related MSC and represent an important paradigm for cancer-induced epigenetic changes in normal cells. Aiming to further explore the importance of this epigenetic deregulation, we performed RNAseq experiments using MSC from healthy donors as well as from MDS and AML patients. This approach not only suggests a profound impact of the epigenetic aberrancies on gene expression, but also allowed us to identify TGFβ as the soluble factor that, released by the malignant cells in the bone marrow, appears to trigger the above-mentioned defects in the MDS- and AML-derived MSC. Indeed, our results show that, when treated with TGFβ, healthy MSC undergo the deregulation of TBX15, PITX2 or HOXB6 and develop some of the observed aberrant phenotypes. Conversely, the treatment of MDS- and AML-derived MSC with a TGFβ antagonist like SD208 can abrogate these effects. Finally, our preliminary DNA methylation data reveal a very similar deregulation in the methylome of MSC from Multiple Myeloma (MM) patients, strongly suggesting that the same scenario could also be common to other hematological malignancies from the lymphoid branch. Citation Format: Manuel Rodríguez-Paredes, Stefanie Geyh, Mahshid Gazorpak, Julian Gutekunst, Felix Bormann, Rainer Haas, Thomas Schröder, Frank Lyko. Epigenomic characterization of MSC from myeloid malignancies [abstract]. In: Proce