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Review Hematologic Malignancies Cytogenetic, Inflammatory, Immunologic, and Infectious Basis for Dysplastic Hematopoeisis Pedro Alcedo, 1 Enrique Andrade, 1 Hussein Hamad, 1,2 and Gustavo Rivero 1,2,3 1. Section of Hematology/Oncology, Baylor St Luke’s Medical Center, Houston, Texas, US; 2. Department of Internal Medicine, Section of Hematology and Oncology, Baylor College of Medicine, Houston, Texas, US; 3. The Dan L Duncan Comprehensive Cancer Center at Baylor College of Medicine, Houston, Texas, US M yelodysplastic syndrome is a heterogeneous immunologic and epigenetic group of myeloid disorders with variable propensity for acute myelogenous leukemia (AML) conversion. Treatment is limited to growth factors, lenalidomide for 5q deletion MDS, and best supportive care for low-risk disease. Allogeneic transplantation and epigenetic therapy are conventionally considered alternatives for high-risk MDS. Inflammation, epigenetic, and cytogenetic participate in disease initiation. However, how these factors interface to develop vulnerability for the disease is largely unknown. In this review, we describe current inflammatory, immunologic, and molecular features that integrate mechanistic potential effectors for MDS. Keywords Myelodysplasia, inflammation, immunity, clonal selection, cytogenetic, epigenetic Disclosure: Pedro Alcedo, Enrique Andrade, Hussein Hamad, and Gustavo Rivero have nothing to declare in relation to this article. No funding was received for the publication of this article. Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit. Received: March 30, 2017 Accepted: May 10, 2017 Citation: Oncology & Hematology Review, 2017;13(2):81–91 Corresponding Author: Gustavo Rivero, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, US. E: garivero@bcm.edu Myelodysplastic syndrome (MDS) is a cytogenetic, epigenetic, and immunological heterogeneous group of myeloid disorders characterized by dysplastic hematopoeisis and propensity for acute myelogenous leukemia (AML) transformation. 1,2 The Surveillance, Epidemiology, and End Results (SEER) Program estimates that risk factors for the disease include, among others, aging, 3 which is frequently associated with myeloid skewed hematopoeisis, 4 male gender, and less characterized, smoking exposure. 5 The revised international prognostic score system (R-IPSS) segregates five subgroups with distinct biologic behavior; however, low risk (very low and low) and high risk (intermediate, high, and very high) categories allow risk stratification for therapy selection. 6 For patients with low-risk disease, gene expression profiling (GEP) highlights defects leading to immune deregulation, and enhanced apoptosis. 7 On the other hand, patients with high risk disease exhibit GEP associated with checkpoint abnormalities and core oncogene activation, such as MYC. 8,9 The World Health Organization (WHO) classification of myeloid disorders allocates disease subgroups that integrate MDS with either multilineage dysplasia (MDS-MLD), MDS single lineage dysplasia (MDS- SLD), MDS with single lineage dysplasia and ring sideroblasts (MDS-RSSLD), MDS with multilineage dysplasia and ring sideroblasts (MDS-RSMLD), MDS with excess blasts-1 (MDS-EB1), and MDS with excess blasts-2 (MDS-EB2). 10 About 70% of MDS patients would present with anemia, however, quantitative and qualitative defects in granulocytes are commonly observed. Neutrophils play an important role in innate defense mechanisms against bacterial infection. Several previous reports highlight not only an increasing incidence but also significant severity of infection in patients with MDS. 11 It is likely that similar defects that initiate dysplastic erythropoiesis originate functional neutrophil abnormalities. In addition, MDS can present with thrombocytopenia, and even functional platelet abnormalities. 12,13 Trilineage quantitative defects emphasize the possibility of multiprogenitor stem cell as initiating event. However, full characterization of MDS stem cell/progenitor has been limited by inability to accurately engraft and propagate human disease in xenograft model. This suggests that the bone marrow microenvironment facilitates initiation and maintenance of the disease. To date, MDS remains enigmatic. It is likely that as novel genomic diagnostic techniques develop, further characterization of MDS-initiating events will improve design and delivery of precision therapy. In this article, we will review the current molecular, inflammatory, and infectious basis for dysplastic hematopoietic failure. Normal hematopoiesis Normal hematopoeisis is a stepwise process that leads to generation of functional red cells, platelets, and granulocytes. Hemopoeitic stem cells (HSCs) proceed through multiple divisions to ensure lifelong provision of differentiated myeloid-lymphoid progenitor (MLP) equipped with potential for stable propagation of self-differentiation programs (see Figure 1). For human blood TOU CH MED ICA L MEDIA 81