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Deregulation of innate immune and inflammatory signaling in myelodysplastic syndromes

Leukemia volume 29, pages 1458–1469 (2015)Cite this article

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Abstract

Myelodysplastic syndromes (MDSs) are a group of heterogeneous clonal hematologic malignancies that are characterized by defective bone marrow (BM) hematopoiesis and by the occurrence of intramedullary apoptosis. During the past decade, the identification of key genetic and epigenetic alterations in patients has improved our understanding of the pathophysiology of this disease. However, the specific molecular mechanisms leading to the pathogenesis of MDS have largely remained obscure. Recently, essential evidence supporting the direct role of innate immune abnormalities in MDS has been obtained, including the identification of multiple key regulators that are overexpressed or constitutively activated in BM hematopoietic stem and progenitor cells. Mounting experimental results indicate that the dysregulation of these molecules leads to abnormal hematopoiesis, unbalanced cell death and proliferation in patients’ BM, and has an important role in the pathogenesis of MDS. Furthermore, there is compelling evidence that the deregulation of innate immune and inflammatory signaling also affects other cells from the immune system and the BM microenvironment, which establish aberrant associations with hematopoietic precursors and contribute to the MDS phenotype. Therefore, the deregulation of innate immune and inflammatory signaling should be considered as one of the driving forces in the pathogenesis of MDS. In this article, we review and update the advances in this field, summarizing the results from the most recent studies and discussing their clinical implications.

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Acknowledgements

This work was supported in part by MD Anderson Cancer Center Support Grant P30 CA016672. GG-M is also supported by the Edward P. Evans Foundation, Fundacion Ramon Areces, grant RP100202 from the Cancer Prevention & Research Institute of Texas (CPRIT) and by philanthropic contributions to MD Anderson’s MDS/AML Moon Shot Program. YW receives support from her DOD CA110791 Discovery Award. MC-C is funded by Fundacion Alfonso Martin-Escudero. DTS is funded by the NIH RO1 grants RO1HL111103, RO1HL114582, RO1DK102759 and by Gabrielle’s Angel Foundation. AV is supported by the Leukemia Lymphoma Society. US is a Research Scholar of the Leukemia & Lymphoma Society and a Diane and Arthur B. Belfer Faculty Scholar in Cancer Research of the Albert Einstein College of Medicine.

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Author notes

  1. I Gañán-Gómez and Y Wei: These authors are co-first authors.

Authors and Affiliations

  1. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    I Gañán-Gómez, Y Wei, S Colla, H Yang, M Cabrero-Calvo, Z S Bohannan & G Garcia-Manero

  2. Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA

    D T Starczynowski

  3. Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    D T Starczynowski

  4. Department of Hematology, University Hospital of Salamanca, Salamanca, Spain

    M Cabrero-Calvo

  5. Division of Hematologic Malignancies, Department of Medicine (Oncology), Einstein/Montefiore Medical Center, New York, NY, USA

    A Verma & U Steidl

  6. Albert Einstein Cancer Center and Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, New York, NY, USA

    A Verma & U Steidl

  7. Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, NY, USA

    A Verma

  8. Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, USA

    U Steidl

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  1. I Gañán-Gómez
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Gañán-Gómez, I., Wei, Y., Starczynowski, D. et al. Deregulation of innate immune and inflammatory signaling in myelodysplastic syndromes. Leukemia 29, 1458–1469 (2015). https://doi.org/10.1038/leu.2015.69

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