Myelodysplastic syndrome and environment

The spectrum of myeloid disorders ranges from aplastic bone marrow failure characterized by an empty bone marrow completely lacking in hematopoiesis to acute myeloid leukemia where the marrow space is replaced by undifferentiated leukemic blasts. Recent advances in the capacity to sequence bulk tumor population as well as at a single cell level has provided significant insight into the stepwise process of transformation to acute myeloid leukemia. Using models of progression in the context of germline predisposition (trisomy 21, GATA2 deficiency, SAMD9/9L syndrome), premalignant states (clonal hematopoiesis and clonal cytopenia of unknown significance) and myelodysplastic syndrome, we review the mechanisms of progression focusing on the hierarchy of clonal mutation and potential roles of transcription factor alterations, splicing factor mutations and the bone marrow environment in progression to acute myeloid leukemia...

The recognition of host genetic factors underlying susceptibility to hematopoietic malignancies has increased greatly over the last decade. Historically, germline predisposition was thought to primarily affect the young. However, emerging data indicate that hematopoietic malignancies that develop in people of all ages across the human lifespan can derive from germline predisposing conditions and are not exclusively observed in younger individuals. The age at which hematopoietic malignancies manifest appears to correlate with distinct underlying biological pathways...

Aplastic anemia (AA) and hypoplastic myelodysplastic syndrome are paradigms of autoimmune hematopoietic failure (AHF). Myelodysplastic syndrome and acute myeloid leukemia are unequivocal myeloid neoplasms (MNs). Currently, AA is also known to be a clonal hematological disease. Genetic aberrations typically observed in MNs are detected in approximately one-third of AA patients. In AA patients harboring MN-related genetic aberrations, a poor response to immunosuppressive therapy (IST) and an increased risk of transformation to MNs occurring either naturally or after IST are predicted...

Transplantation of HLA and/or KIR mismatched allogeneic hematopoietic stem cells can lead NK cells to different states of activation/inhibition or education/resetting and change anti-tumor immunosurveillance. In this study, we used molecular relapse monitoring to investigate a correlation between either missing ligand recognition or variation of the cognate iKIR-HLA pairs with clinical outcomes in patients with hematological malignancies requiring allogeneic hematopoietic stem cell transplantation (allo-HSCT)...

Myeloid malignancies are composed of multiple clonal hematopoietic disorders, including myelodysplastic syndrome, myeloproliferative neoplasms, and acute myeloid leukemia. Inflammation is already known to play an important role in the pathogenesis of an extensive variety of malignancies, and its significance in myeloid malignancies is becoming more widely recognized. Specifically, cell-intrinsic and -extrinsic activation of the innate immune signaling pathway, as well as elevation of proinflammatory cytokines via innate immune signaling downstream signaling, have been demonstrated...

During aging, the onset of mutations at low frequency in hematopoietic cells or clonal hematopoiesis of indeterminate significance favors the evolution towards hemopathies such as myelodysplastic syndromes or acute leukemias, but also cardiovascular diseases and other pathologies. Acute or chronic inflammation related to age influences the clonal evolution and the immune response. Conversely, mutated hematopoietic cells create an inflammatory bone marrow environment facilitating their expansion. Various pathophysiological mechanisms depending on the type of mutation produce the diversity of phenotypes...

BACKGROUND: In myelodysplastic syndromes (MDS), in addition to disease-related symptoms, many adverse events are associated with anticancer agents, myeloablative conditioning (MAC), and allogeneic hematopoietic stem cell transplantation (allo-HSCT). Isolation and bed rest in a clean room severely limit physical activity, resulting in cardiopulmonary and muscle weakness. In addition, post-transplant patients may experience general fatigue, gastrointestinal symptoms, and infections associated with a weakened immune system, as well as graft-versus-host disease, which causes further decline in physical function and activities of daily living (ADL)...

The human immunodeficiency virus (HIV) is a retrovirus that infects a subset of T lymphocytes referred to as CD4 T-helper cells. This insult to the quantity and quality of T lymphocytes leads to a significant compromise of the immune system and the development of an environment of abnormal immune activation. This aberrancy in the immune system increases the susceptibility to developing various malignancies. Hematological abnormalities like cytopenias are among the most common complications of HIV and acquired immunodeficiency syndrome (AIDS)-related lymphoid malignancies...

Myelodysplastic syndromes (MDS) and their progression to secondary acute myeloid leukemia (sAML) are associated with an altered protein expression including extracellular matrix (ECM) components thereby promoting an inflammatory environment. Since the role of the proteoglycan biglycan (BGN) as an inflammatory mediator has not yet been investigated in both diseases and might play a role in disease progression, its expression and/or function was determined in cell lines and bone marrow biopsies (BMBs) of MDS and sAML patients and subpopulations of MDS stem cells by Western blot and immunohistochemistry...

The BM, the major hematopoietic organ in humans, consists of a pleiomorphic environment of cellular, extracellular, and bioactive compounds with continuous and complex interactions between them, leading to the formation of mature blood cells found in the peripheral circulation. Systemic and local inflammation in the BM elicit stress hematopoiesis and drive hematopoietic stem cells (HSCs) out of their quiescent state, as part of a protective pathophysiologic process. However, sustained chronic inflammation impairs HSC function, favors mutagenesis, and predisposes the development of hematologic malignancies, such as myelodysplastic syndromes (MDS)...

Myelodysplastic syndrome is one of the main hematological malignancies that threaten the health of the elderly. However, biomarkers which predict the progression and prognosis of MDS are still controversial and puzzling. FOXO1 gene plays an important role in a variety of intracellular functions, including tumor suppression and cellular immune regulation. However, there is no research report on the correlation between FOXO1 and the clinical features of MDS including immune environment. In this study, we observed that FOXO1 expression is associated with neutrophil count, blasts, chromosome and different MDS scoring systems...

Myelodysplastic syndromes (MDS) can be associated with auto-immune disorders, possibly due to the proinflammatory environment in the bone marrow niche. Noticeably, TET2 mutations has been reported to be associated with an increased risk of auto-immune disease. On the other hand, auto-immune myopathies are associated with solid and hematologic neoplasia but associations between MDS and inflammatory myopathies are rare and only few cases have been reported so far. We report here the case of a 66-year-old patient suffering from a necrotizing myopathy diagnosed 7 years after the onset of a MDS with multilineage dysplasia (MDS-DML) and TET2 mutations...

INTRODUCTION: Healthcare-associated infections (HAIs) impact morbidity, mortality, and hospitalization costs. They usually have a bacterial aetiology, and it is still unknown the participation of viruses in those instances. This study aimed to evaluate the prevalence and clinical findings in patients with HAIs caused by respiratory viruses. METHODS: An observational, analytical, cross-sectional study was conducted to evaluate patients with a viral nosocomial respiratory infection, occurring between January/2013 and December/2019...

Myeloid neoplasms with germline predisposition have recently been added as distinct provisional entities in the 2017 revision of the World Health Organization's classification of tumors of hematopoietic and lymphatic tissue. Individuals with germline predisposition have increased risk of developing myeloid neoplasms-mainly acute myeloid leukemia and myelodysplastic syndrome. Although the incidence of myeloid neoplasms with germline predisposition remains poorly defined, these cases provide unique and important insights into the biology and molecular mechanisms of myeloid neoplasms...

MOTIVATION: Alternative splicing contributes to the diversity of RNA found in biological samples. Current tools investigating patterns of alternative splicing check for coordinated changes in the expression or relative ratio of RNA isoforms where specific isoforms are up- or downregulated in a condition. However, the molecular process of splicing is stochastic and changes in RNA isoform diversity for a gene might arise between samples or conditions. A specific condition can be dominated by a single isoform, while multiple isoforms with similar expression levels can be present in a different condition...

Background: Myelodysplastic syndrome (MDS) is a group of disorders involving hemopoietic dysfunction leading to leukemia. Although recently progress has been made in identifying underlying genetic mutations, many questions still remain. Animal models of MDS have been produced by introduction of specific mutations. However, there is no spontaneous mouse model of MDS, and an animal model to simulate natural MDS pathogenesis is urgently needed. Methods: In characterizing the genetically diverse mouse strains of the Collaborative Cross (CC) we observed that one, designated JUN, had abnormal hematological traits...

Imetelstat (GRN163L) is a potent and specific telomerase inhibitor currently in clinical development for the treatment of hematological malignancies such as myelofibrosis and myelodysplastic syndrome. It is a 13-mer N3'-P5' thio-phosphoramidate oligonucleotide covalently functionalized at the 5'-end with a palmitoyl lipid moiety through an aminoglycerol linker. As a competitive inhibitor of human telomerase, imetelstat directly binds to the telomerase RNA component sequence (hTR) in the catalytic site of the enzyme and acts as a direct competitor of human telomere binding...

Natural killer (NK) cells are key innate immunity effectors that play a major role in malignant cell destruction. Based on expression patterns of CD16, CD56, CD57, and CD94, three distinct NK cell maturation stages have been described, which differ in terms of cytokine secretion, tissue migration, and the ability to kill target cells. Our study addressed NK cell maturation in bone marrow under three conditions: a normal developmental environment, during pre-leukemic state (myelodysplastic syndrome, MDS), and during leukemic transformation (acute myeloblastic leukemia, AML)...

Pediatric myelodysplastic syndromes (MDS) are a heterogeneous disease group associated with impaired hematopoiesis, bone marrow hypocellularity, and frequently have deletions involving chromosome 7 (monosomy 7). We and others recently identified heterozygous germline mutations in SAMD9 and SAMD9L in children with monosomy 7 and MDS. We previously demonstrated an antiproliferative effect of these gene products in non-hematopoietic cells, which was exacerbated by their patient-associated mutations. Here, we used a lentiviral overexpression approach to assess the functional impact and underlying cellular processes of wild-type and mutant SAMD9 or SAMD9L in primary mouse or human hematopoietic stem and progenitor cells (HSPC)...

Cellular senescence constitutes a permanent state of cell cycle arrest in proliferative cells induced by different stresses. The exploration of tumor pathogenesis and therapies has been a research hotspot in recent years. Cellular senescence is a significant mechanism to prevent the proliferation of potential tumor cells, but it can also promote tumor growth. Increasing evidence suggests that cellular senescence is involved in the pathogenesis and development of hematological malignancies, including leukemia, myelodysplastic syndrome (MDS) and multiple myeloma (MM)...