Myelodysplastic syndrome and environment

Myelodysplastic syndrome (MDS) is a malignancy that disrupts normal blood cell production and commonly affects our ageing population. MDS patients are diagnosed using an invasive bone marrow biopsy and high-risk MDS patients are treated with hypomethylating agents (HMAs) such as decitabine and azacytidine. However, these therapies are only effective in 50% of patients, and many develop resistance to therapy, often resulting in bone marrow failure or leukemic transformation. Therefore, there is a strong need for less invasive, diagnostic tests for MDS, novel markers that can predict response to therapy and/or patient prognosis to aid treatment stratification, as well as new and effective therapeutics to enhance patient quality of life and survival...

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that play a critical immunosuppressive role in the tumour micro-environment. Although biological research on MDSCs has made progress, the relationship between the secretion of cytokines by MDSCs and poor prognosis is not clear, and there are no criteria to measure the functional status of MDSCs. Here, we detected the mRNA expression of IL-10, IL-12, TGF-β and TNF-α in MDSCs and the levels of these cytokines in MDSC culture supernatants of patients with myelodysplastic syndromes, and quantified the functional status of MDSCs by IL-10/IL-12 ratio and TGF-β/TNF-α ratio...

Hematological diseases after solid organ transplant (SOT) are an emerging issue as the number of long-term SOT survivors increases. Expertise in managing patients requiring allogeneic hematopoietic stem cell transplantation (HSCT) after SOT from independent donors is needed; however, clinical reports of HSCT after SOT are limited, and the feasibility and risk are not well understood. In particular, HSCT in prior lung transplant recipients is thought to be complicated as the lung is immunologically distinct and is constantly exposed to the surrounding environment...

Clonal hematopoiesis (CH) is associated with age and an increased risk of myeloid malignancies, cardiovascular risk, and all-cause mortality. We tested for CH in a setting where hematopoietic stem cells (HSCs) of the same individual are exposed to different degrees of proliferative stress and environments, ie, in long-term survivors of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and their respective related donors (n = 42 donor-recipient pairs). With a median follow-up time since allo-HSCT of 16 years (range, 10-32 years), we found a total of 35 mutations in 23 out of 84 (27...

Bone marrow stromal cells from patients with myelodysplastic syndrome (MDS) display a senescence phenotype, but the underlying mechanism has not been elucidated. Pro-inflammatory signaling within the malignant clone and the bone marrow microenvironment has been identified as a key pathogenetic driver of MDS. Our study revealed that S100A9 is highly-expressed in lower-risk MDS. Moreover, normal primary mesenchymal stromal cells (MSCs) and the human stromal cell line HS-27a co-cultured with lower-risk MDS bone marrow mononuclear cells acquired a senescence phenotype...

Pathological phenotypes of myeloid neoplasms are closely related to genetic/chromosomal abnormalities of neoplastic cells whereas the bone marrow microenvironment, including stromal elements and hematopoietic stem cell niche cells, have a great influence on the differentiation/proliferation of both hematopoietic and neoplastic cells. The pathology of myeloid neoplasms might be generated through the interaction of hematopoietic (stem) cells and stromal cells. The present study aims to provide the morphological/functional aspects of the bone marrow environment in myeloid neoplasms...

Established cell culture systems have failed to accurately recapitulate key features of terminal erythroid maturation, hampering our ability to in vitro model and treat diseases with impaired erythropoiesis such as myelodysplastic syndromes with ring sideroblasts (MDS-RS). We developed an efficient and robust three-dimensional (3D) scaffold culture model supporting terminal erythroid differentiation from both mononuclear (MNC) or CD34+ -enriched primary bone marrow cells from healthy donors and MDS-RS patients...

The bone marrow of patients with low-risk myelodysplastic syndromes (MDS) is often an inflammatory environment and associated with an active cellular immune response. An active immune response generally contributes to antitumor responses and may prevent disease progression. However, chronic immune stimulation can also induce cell stress, DNA damage and contribute to the pathogenesis of MDS. The protective mechanisms against excessive immune activation are therefore an important aspect of the pathophysiology of MDS and characterizing them may help us to better understand the fine balance between protective and destabilizing inflammation in lower-risk disease...

Chronic myelomonocytic leukemia (CMML) is a myeloid hematological malignancy with overlapping features of myelodysplastic syndromes (MDSs) and myeloproliferative neoplasms (MPNs). The knowledge of the role of the tumor microenvironment (TME), particularly mesenchymal stromal cells (MSCs), in MDS pathogenesis is increasing. Generally, cancer is associated with a procoagulant state participating in tumor development. Monocytes release procoagulant, tissue factor (TF)-bearing microparticles. We hypothesized that MSCs and clonal monocytes release procoagulant extracellular vesicles (EVs) within the CMML TME, inducing a procoagulant state that could modify hematopoietic stem cell (HSC) homeostasis...

BACKGROUND: Accumulating evidence has indicated that the dysregulation of immunological environment has an important role in the pathogenesis of myelodysplastic syndromes (MDS). The previous studies about the levels of the inflammatory cytokines in MDS, such as TNF-α, IFN-γ, IL-6, IL-8, and IL-17, have yielded controversial results. Thus, we performed a meta-analysis to assess the levels of these inflammatory cytokines in MDS. METHODS: A systematic search in PubMed, MEDLINE, Cochrane Library, Web of Science, CNKI, and CBM was conducted to find eligible studies...

Aplastic anemia (AA) is an autoimmune-mediated bone marrow failure syndrome. While AA is not a malignant disease, clonal hematopoiesis is commonly detected via next-generation sequencing and single nucleotide polymorphism (SNP) array. Clonal hematopoiesis in AA has been confirmed by the detection of classic X chromosome skewing, PNH clones, UPD6p, and various mutations. The most frequent genetic events in AA are UPD6p and somatic mutations in BCOR/BCORL1, PIGA, DNMT3A, and ASXL1. While some mutations are common between patients with AA and healthy elderly donors, UPD6p and PIGA mutations are specific to clonal cells in AA, which need to manage their highly autoimmune extrinsic environment...

Elucidation of how the differentiation of hematopoietic stem and progenitor cells (HSPCs) is reconfigured in response to the environment is critical for understanding the biology and disorder of hematopoiesis. Here we found that the transcription factors (TFs) Bach2 and Bach1 promoted erythropoiesis by regulating heme metabolism in committed erythroid cells to sustain erythroblast maturation and by reinforcing erythroid commitment at the erythro-myeloid bifurcation step. Bach TFs repressed expression of the gene encoding the transcription factor C/EBPβ, as well as that of its target genes encoding molecules important for myelopoiesis and inflammation; they achieved the latter by binding to their regulatory regions also bound by C/EBPβ...

Clinical features of myelodysplastic syndromes (MDS) could be influenced by many factors, such as disease intrinsic factors (e.g., morphologic, cytogenetic, molecular), extrinsic factors (e.g, management, environment), and ethnicity. Several previous studies have suggested such differences between Asian and European/USA countries. In this study, to elucidate potential differences in primary untreated MDS between Japanese (JPN) and Caucasians (CAUC), we analyzed the data from a large international database collected by the International Working Group for Prognosis of MDS (300 and 5838 patients, respectively)...

After the creation of the Academy of Medical Sciences of Ukraine in 1993 the Research Center for Radiation Medicine was among the first institutions to join the Academy (fig. 1). Estab lishing the Academy was among the first steps of the independent Ukrainian government and aimed to provide a high level health care for population. It was extremely needed for the minimization of Chornobyl medical consequences. This choice was related to a growing recognition of the scientific research in fulfilling the Сenter's mission - study of the effects of low dose radiation on human body and radiation protection of the exposed population...

Therapy-related myeloid neoplasms (t-MN) arise as a late effect of chemotherapy and/or radiation administered for a primary condition, typically a malignant disease, solid organ transplant or autoimmune disease. Survival is measured in months, not years, making t-MN one of the most aggressive and lethal cancers. In this Review, we discuss recent developments that reframe our understanding of the genetic and environmental aetiology of t-MN. Emerging data are illuminating who is at highest risk of developing t-MN, why t-MN are chemoresistant and how we may use this information to treat and ultimately prevent this lethal disease...

Mucormycosis of the frontal sinus are rarely seen in day to day clinical practice. Although this fungus is commonly found in the environment, the disease is usually prevented by the immune system and is hence rare. Well-recognized risk factors for the disease include diabetes mellitus, leukemia, aplastic anemia, myelodysplastic syndrome, blood dyscrasias, and immunosuppressive therapy in organ transplantation, renal disease, sepsis, and severe burns. The disease is primarily found in those who are immunocompromised, but it may also manifest in immuno competent persons...

Myelodysplastic syndromes (MDS) are clonal neoplasms of aging that are associated with BM failure, related cytopenias, fatigue, susceptibility to infections, bruising, bleeding, a shortened lifespan, and a propensity for leukemic transformation. Most frail, elderly patients are not candidates for curative allogeneic BM transplantations and instead receive expectant management, supportive blood transfusions, or empirical, nontargeted therapy. It has been known for some time that MDS arises in an abnormal BM immune environment; however, connections have only recently been established with recurring MDS-associated mutations...

Similar to their healthy counterpart, malignant hematopoietic stem cells in myeloid malignancies, such as myeloproliferative neoplasms, myelodysplastic syndromes, and acute myeloid leukemia, reside in a highly complex and dynamic cellular microenvironment in the bone marrow. This environment provides key regulatory signals for and tightly controls cardinal features of hematopoietic stem cells (HSCs), including self-renewal, quiescence, differentiation, and migration. These features are essential to maintaining cellular homeostasis and blood regeneration throughout life...

Natural killer (NK) cell licensing status depends on clonal expression of inhibitory killer cell immunoglobulin-like receptors (iKIR) and short term HLA environment. Licensed NK cells are more efficient in tumor killing than unlicensed NK cells. Cognate KIR-HLA pairs in hematopoietic stem cell transplant (HSCT) donor and recipient are decisive for the possible change in the NK cell licensing status after HSCT. We assessed clinical outcomes in 297 patients with lymphoproliferative or myeloproliferative malignancies, or myelodysplastic syndrome in a model with upward licensing, downward resetting, and unchanged licensing genetics status after T cell replate HSCT from unrelated donors...

Paroxysmal nocturnal hemoglobinuria (PNH), a disease characterized by intravascular hemolysis, thrombosis, and bone marrow failure, is associated with mutations in the PIG-A gene, resulting in a deficiency of glycosylphosphatidylinositol-anchored proteins. Many hypotheses have been posed as to whether PNH and PIG-A mutations result in an intrinsic survival benefit of CD55(-)/CD59(-) cells or an extrinsic permissive environment that allows for their clonal expansion within the bone marrow compartment. Recent data have identified the concurrence of PIG-A mutations with additional genetic mutations associated with myeloproliferative disorders, suggesting that some presentations of PNH are the result of a stepwise progression of genetic mutations similar to other myelodysplastic or myeloproliferative syndromes...