Immune dysregulation in myelodysplastic syndrome

Myelodysplastic syndrome (MDS) represents one of the most challenging health-related problems in the elderly. Characterized by dysplastic morphology in the bone marrow in association with ineffective hematopoiesis, pathophysiological causes of this disease are diverse including genetic abnormalities within myeloid progenitors, altered epigenetics, and changes in the bone marrow microenvironment. The concept that T-cell mediated autoimmunity contributes to bone marrow failure has been widely accepted due to hematologic improvement after immunosuppressive therapy (IST) in a subset of patients. Currently, IST for MDS primarily involves anti-thymocyte globulin (ATG)-based regimens in which responsiveness is strongly associated with younger (under 60 years) age at disease onset. In such cases, progressive cytopenia may occur as a consequence of expanded self-reactive CD8+ cytotoxic T lymphocytes (CTLs) that suppress hematopoietic progenitors. Although most hematologists agree that IST can offer durable hematologic remission in younger patients with MDS, an international clinical study and a better understanding of the molecular mechanisms contributing to the expansion of self-reactive CTLs is crucial. In this review, data accumulated in the US, Europe, and Asia will be summarized to provide insight and direction for a multi-center international trial

Bone Marrow Mononuclear Cells Up-Regulate Toll-Like Receptor Expression and Produce Inflammatory Mediators in Response to Cigarette Smoke Extract

Several reports link cigarette smoking with leukemia. However, the effects of cigarette smoke extract (CSE) on bone marrow hematopoiesis remain unknown. The objective of this study was to elucidate the direct effects of cigarette smoke on human bone marrow hematopoiesis and characterize the inflammatory process known to result from cigarette smoking. Bone marrow mononuclear cells (BMCs) from healthy individuals when exposed to CSE had significantly diminished CFU-E, BFU-E and CFU-GM. We found increased nuclear translocation of the NF-κB p65 subunit and, independently, enhanced activation of AKT and ERK1/2. Exposure of BMCs to CSE induced IL-8 and TGF-β1 production, which was dependent on NF-κB and ERK1/2, but not on AKT. CSE treatment had no effect on the release of TNF-α, IL-10, or VEGF. Finally, CSE also had a significant induction of TLR2, TLR3 and TLR4, out of which, the up-regulation of TLR2 and TLR3 was found to be dependent on ERK1/2 and NF-κB activation, but not AKT. These results indicate that CSE profoundly inhibits the growth of erythroid and granulocyte-macrophage progenitors in the bone marrow. Further, CSE modulates NF-κB- and ERK1/2-dependent responses, suggesting that cigarette smoking may impair bone marrow hematopoiesis in vivo as well as induce inflammation, two processes that proceed malignant transformation

Role of Polyamines in Immune Cell Functions

The immune system is remarkably responsive to a myriad of invading microorganisms and provides continuous surveillance against tissue damage and developing tumor cells. To achieve these diverse functions, multiple soluble and cellular components must react in an orchestrated cascade of events to control the specificity, magnitude and persistence of the immune response. Numerous catabolic and anabolic processes are involved in this process, and prominent roles for l-arginine and l-glutamine catabolism have been described, as these amino acids serve as precursors of nitric oxide, creatine, agmatine, tricarboxylic acid cycle intermediates, nucleotides and other amino acids, as well as for ornithine, which is used to synthesize putrescine and the polyamines spermidine and spermine. Polyamines have several purported roles and high levels of polyamines are manifest in tumor cells as well in autoreactive B- and T-cells in autoimmune diseases. In the tumor microenvironment, l-arginine catabolism by both tumor cells and suppressive myeloid cells is known to dampen cytotoxic T-cell functions suggesting there might be links between polyamines and T-cell suppression. Here, we review studies suggesting roles of polyamines in normal immune cell function and highlight their connections to autoimmunity and anti-tumor immune cell function

Immune dysregulation in myelodysplastic syndrome

Myelodysplastic syndrome (MDS) represents one of the most challenging health-related problems in the elderly. Characterized by dysplastic morphology in the bone marrow in association with ineffective hematopoiesis, pathophysiological causes of this disease are diverse including genetic abnormalities within myeloid progenitors, altered epigenetics, and changes in the bone marrow microenvironment. The concept that T-cell mediated autoimmunity contributes to bone marrow failure has been widely accepted due to hematologic improvement after immunosuppressive therapy (IST) in a subset of patients. Currently, IST for MDS primarily involves anti-thymocyte globulin (ATG)-based regimens in which responsiveness is strongly associated with younger (under 60 years) age at disease onset. In such cases, progressive cytopenia may occur as a consequence of expanded self-reactive CD8 + cytotoxic T lymphocytes (CTLs) that suppress hematopoietic progenitors. Although most hematologists agree that IST can offer durable hematologic remission in younger patients with MDS, an international clinical study and a better understanding of the molecular mechanisms contributing to the expansion of selfreactive CTLs is crucial. In this review, data accumulated in the US, Europe, and Asia will be summarized to provide insight and direction for a multi-center international trial. Overview of myelodysplastic syndrom

Abstract 5417: Expansion of effector regulatory T-cells represents a novel and independent prognostic factor marking escape from immune surveillance in Myleodysplastic Syndrome

Abstract Myelodysplastic syndromes (MDS) refer to a group of pathophysiologically diverse hematopoietic neoplasms associated with cytopenias, myeloid dysplasia, and variable acute myeloid leukemia risk. Response to immunosuppressive therapies (IST) in a subset of younger patients classified as lower-risk by the International Prognostic Scoring System (IPSS) suggests that inflammation and immune reactivity in the bone marrow likely plays a role in early MDS pathogenesis. Conversely, higher-risk patients with more established disease do not respond to IST. Previous reports of increased regulatory T-cells (Tregs) in these patients suggest that immune escape may be required for progression to higher-risk disease. The distinct changes in the role of the immune system between lower and higher-risk disease suggests that MDS may progress according to established principles of cancer immuno-editing involving elimination, equilibrium and escape phases. Because Treg suppressive activity is dependant upon auto-antigen presentation, we hypothesized that analyzing the activation state of Tregs may better reflect the onset of tumor-induced immune suppression in MDS and have better prognostic utility than measuring total Treg numbers alone. Here, we use a panel of surface markers on Tregs that are normally employed to distinguish effector and memory populations among conventional T-cells and analyzed the resulting subpopulations for associations with clinical features including overall survival (OS) among patients predominantly classified as lower-risk. Abnormal numbers of Treg subtypes were seen in 18 (34.6%) of 52 patients compared to age-matched controls. The most prominent and unique change in MDS patients was an expansion of effector Tregs (TregEff) which was significantly associated with anemia (p=0.046) and reduced hemoglobin (p=0.038). This group of patients had increased blast percentage (p=0.006) and displayed worse OS by Cox-regression (HR 4.3, 95% CI 1.6-11.6, p=0.004) independent of IPSS (p=0.002) and the MD Anderson Scoring System (MDAS) (p=0.047). Increased TregEff numbers were not dependant on total Treg numbers. Rather, they came at the expense of central memory Tregs suggesting that Treg “class switching” may reflect active presentation of auto-antigens. When isolated, TregEff cells displayed increased suppressive capacity compared to other Treg subpopulations and heightened TregEff numbers were limited to patients with elevated blasts (tumor burden), suggesting a mechanistic link between immune-evasion and MDS progression. The MDAS significantly refined OS estimates (p<0.001) compared to IPSS. Using the MDAS, OS in higher-risk patients could be further stratified using TregEff numbers (p=0.018), suggesting that enumeration of TregEff cells may improve prognostication and impact therapeutic selection in MDS. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5417. doi:1538-7445.AM2012-541

Clonal hematopoiesis of indeterminate potential and its impact on patient trajectories after stem cell transplantation.

Clonal hematopoiesis of indeterminate potential (CHIP) is a recently identified process where older patients accumulate distinct subclones defined by recurring somatic mutations in hematopoietic stem cells. CHIP's implications for stem cell transplantation have been harder to identify due to the high degree of mutational heterogeneity that is present within the genetically distinct subclones. In order to gain a better understanding of CHIP and the impact of clonal dynamics on transplantation outcomes, we created a mathematical model of clonal competition dynamics. Our analyses highlight the importance of understanding competition intensity between healthy and mutant clones. Importantly, we highlight the risk that CHIP poses in leading to dominance of precancerous mutant clones and the risk of donor derived leukemia. Furthermore, we estimate the degree of competition intensity and bone marrow niche decline in mice during aging by using our modeling framework. Together, our work highlights the importance of better characterizing the ecological and clonal composition in hematopoietic donor populations at the time of stem cell transplantation