Elsevier

Molecular Genetics and Metabolism

Volume 116, Issues 1–2, September–October 2015, Pages 24-28
Molecular Genetics and Metabolism

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Biology of the bone marrow microenvironment and myelodysplastic syndromes

https://doi.org/10.1016/j.ymgme.2015.07.004Get rights and content

Highlights

  • The bone marrow microenvironment plays a critical role in the pathogenesis of MDS.

  • Characterization of molecular pathways that contribute to MDS could lead to identification of novel approaches to treat MDS.

  • Inflammatory signals in the bone marrow determine hematopoietic stem cell fate and are aberrantly regulated in MDS hematopoietic stem cells.

  • Hypoxia is important for normal hematopoietic stem cell development and potentially plays a role in MDS.

  • Dysregulation of inflammatory signaling, including upregulation of TNFalpha, is associated with the development of acquired and inherited bone marrow failure syndromes. Dysregulation of inflammatory signaling contributes to the pathogenesis of MDS through both direct mechanisms on HSCs and by altering the bone marrow microenvironment.

Abstract

Myelodysplastic syndromes (MDS) are characterized by cytopenias resulting from ineffective hematopoiesis with a predisposition to transform to acute myeloid leukemia (AML). Recent evidence suggests that the hematopoietic stem cell microenvironment contributes to the pathogenesis of MDS. Inflammation and hypoxia within the bone marrow are key regulators of hematopoietic stem and progenitor cells that can lead to several bone marrow failure syndromes, including MDS. In this brief review, we provide an overview of the clinical and molecular features of MDS, the bone marrow microenvironment, and specific pathways that lead to abnormal blood cell development in MDS. Characterization of key steps in the pathogenesis of MDS will lead to new approaches to treat patients with this disease.

Introduction

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal disorders characterized by ineffective hematopoiesis in the bone marrow leading to cytopenias in the blood and a predisposition to acute myeloid leukemia (AML) [1], [2], [3], [4]. The categorization of subclasses of MDS is based on the percentage of leukemia blasts in the peripheral blood and the bone marrow, the number and type of dysplastic cell lineages, the presence of ringed sideroblasts, and cytogenetic abnormalities. Low, intermediate or high-risk MDS are classified using the revised International Prognostic Scoring System [5], [6]. The majority of MDS patients are diagnosed at greater than 70 years of age. A number of factors including environmental, genetic and prior exposure to chemotherapy or radiation therapies are associated with the development of MDS [7]. In addition, there are a number of inherited bone marrow failure syndromes including Fanconi anemia (FA), Shwachman–Diamond syndrome (SDS), and dyskeratosis congenital (DC) that often develop during childhood and predispose patients to the development of MDS at an early age [7], [8].

A variety of morphological, genetic, and clinical features have been identified that distinguish pediatric MDS from adult MDS and have been previously discussed in detail [9]. Although relatively uncommon in children, de novo and secondary MDS are often the first presentation of an inherited bone marrow failure syndrome. Unlike in adults, pediatric MDS are more often associated with monosomy 7 and a hypocellular bone marrow. Refractory cytopenia is more common than refractory anemia, which is seen in the elderly [9]. Thus, there are biological and clinical aspects of pediatric MDS that are different from adult MDS.

Significant advances have been made to understand the pathogenesis of MDS to explain the spectrum of this disease. In addition to cytogenetic abnormalities including del (5q), − 7 or del(7q), and + 8, defects have been identified in RNA splicing machinery, epigenetic regulation of gene expression, and specific signaling pathways, including p38 Mitogen Activated Protein Kinase (MAPK) and Tissue Necrosis Factor alpha (TNFalpha) [3]. Somatic mutations have been identified in hematopoietic stem cells from MDS patients and most likely contribute to the pathogenesis of the disease. Approximately 80% of MDS patients have a somatic mutation in their hematopoietic stem cells. Mutations in p53, EZH2, ETV6, RUNX1, and ASXL1, in MDS patients have been associated with a poor prognosis [4]. In particular, p53 mutations predict patients who will progress to AML.

Treatment of MDS depends on the severity of the disease. For low-risk MDS, supportive care has been the primary mode of treatment, including growth factors, transfusions, and antibiotic therapy [4]. For high risk disease, hypomethylating agents (decitabine and 5-azacytidine), immunomodulatory drugs (lenalidomide), and chemotherapy (daunomycin, cytarabine) are often used. High dose chemotherapy and stem cell transplantation can produce long-term remission in high-risk MDS patients.

Section snippets

Bone marrow microenvironment and MDS

The bone marrow is comprised of hematopoietic stem cells (HSCs) existing within a complex and dynamic microenvironment with multiple cellular and molecular factors that regulate hematopoiesis under physiologic and pathophysiologic conditions. The delicate interplay between the hematopoietic stem and progenitor cells, stromal cells, and cytokines or chemokines secreted within the microenvironment is needed to maintain hematopoiesis. Multiple cellular components of the bone marrow

Hypoxia and MDS

In addition to the cellular components of the HSC/MDS niche mentioned above, hypoxia, or low oxygen availability, is a prominent molecular feature of the bone marrow microenvironment that contributes to both normal and malignant hematopoiesis. Relative to most tissues, the bone marrow resides in a particularly hypoxic microenvironment. Oxygen tensions within the bone marrow cavity range from 0.6% to 4.2% O2, whereas oxygen tensions in most other adult tissues range from 2–9% O2 [16], [17].

Inflammation and immune suppression in MDS

The role of inflammation and immune suppression is becoming increasingly recognized as an important factor in the pathogenesis of bone marrow failure syndromes, including MDS, DBA, and FA [33], [34]. Dysregulation of cytokine expression in MDS bone marrow contributes to suppression of both ineffective hematopoiesis and malignant clone immune escape. The expression of TNFalpha, TGFbeta, IFNgamma, IL-4, IL-6, IL-7, and IL-10 is abnormally regulated in some MDS patients [1], [35]. TNFalpha has

Ribosomal deficiency, MDS, and inflammatory response

One of the most common chromosomal abnormalities in adult MDS is (del)5q. Somatic chromosomal deletions in 5q lead to the development of MDS that is characterized by a defect in erythroid differentiation. Ebert et al. employed an siRNA approach to identify downregulated genes that would phenocopy the hematopoietic defects associated with 5q deletion. These studies revealed that partial loss of the ribosomal protein subunit 14 (RPS14) was sufficient to phenocopy the disease in hematopoietic

Targeting the microenvironment for treatment of MDS

Several approaches to decrease inflammation in the bone marrow of MDS patients have been taken. Unfortunately, immune modulators have variable responses in MDS patients. Antithymocyte globulin and cyclosporine alone or in combination have responses between 0 and 30% [1]. One study showed that lenalidomide is effective in 83% of patients with del(5q) MDS, while hypomethylating agents seem to be more effective in MDS patients with greater numbers of blasts in the bone marrow [55]. An obvious

Acknowledgements

K.M.S. is supported by the NIH (R01 HL75826, R01 GM087305, DOD BMFRP Idea Award BM110060), Leukemia and Lymphoma Society of America Screen to Lead Program (SLP-8009-15), Hyundai Hope on Wheels (#02500CA), Stanford SPARK/Child Health Research Institute, A.N. (ASH Scholar Award, K08 DK090145-01A1, CHRI Pilot Early Career Award), J.K.P. (T32DK098132, Paul and Yuanbi Ramsay Endowed Postdoctoral Fellowship, Child Health Research Institute and the Stanford CTSA UL1 TR001085).

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