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Ineffective hematopoiesis is a fundamental process leading to the pathogenesis of myelodysplastic syndromes (MDS). However, the pathobiological mediators of ineffective hematopoiesis in MDS remain unclear. Here, we demonstrated that overwhelming mitochondrial fragmentation in mutant hematopoietic stem cells and progenitors (HSC/P) triggers ineffective hematopoiesis in MDS. Mouse modeling of CBL exon deletion with RUNX1 mutants, previously unreported comutations in patients with MDS, recapitulated not only clinically relevant MDS phenotypes but also a distinct MDS-related gene signature. Mechanistically, dynamin-related protein 1 (DRP1)–dependent excessive mitochondrial fragmentation in HSC/Ps led to excessive reactive oxygen species production, induced inflammatory signaling activation, and promoted subsequent dysplasia formation and impairment of granulopoiesis. Mitochondrial fragmentation was generally observed in patients with MDS. Pharmacologic inhibition of DRP1 attenuated mitochondrial fragmentation and rescued ineffective hematopoiesis phenotypes in mice with MDS. These findings provide mechanistic insights into ineffective hematopoiesis and indicate that dysregulated mitochondrial dynamics could be a therapeutic target for bone marrow failure in MDS. Significance: We demonstrated that excessive mitochondrial fragmentation is a fundamental pathobiological phenomenon that could trigger dysplasia formation and ineffective hematopoiesis in MDS. Our findings provide mechanistic insights into ineffective hematopoiesis and suggest dysregulated mitochondrial dynamics as a therapeutic target for treating MDS. This article is highlighted in the In This Issue feature, p. 1

Ineffective hematopoiesis is the major characteristic of early myelodysplastic syndromes. Its pathophysiology relies on a diversity of mechanisms supported by genetic events that develop in aging hematopoietic stem cells. Deletion and mutations trigger epigenetic modifications, and co-transcriptional and post-transcriptional deregulations of gene expression. Epistatic interactions between mutants may aggravate the phenotype. Amplification of minor subclones containing mutations that promote their growth and suppress the others drives the clonal evolution. Aging also participates in reprogramming the immune microenvironment towards an inflammatory state, which precedes the expansion of immunosuppressive cells such as Tregs and myeloid-derived suppressive cells that alters the anti-tumor response of effector cells. Integrating biomarkers of transcription/translation deregulation and immune contexture will help the design of personalized treatments.

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic stem cell diseases characterized by cell dysplasia, ineffective hematopoiesis and risk of transformation to acute myeloid leukemia (AML). The median age of 75 years at diagnosis is associated with the presence of comorbidities, which preclude intensive therapies like allogeneic hematopoietic stem cell transplantation in most MDS patients. Risk stratification using the (Revised) International Prognostic Scoring System (IPSS/IPSS-R) is necessary to plan individualized treatment.Luspatercept (ACE-536), a specific activin receptor fusion protein, promotes late-stage erythropoiesis. Two clinical trials, PACE-MDS (phase 2) and MEDALIST (phase 3), yielded positive results in terms of improved hemoglobin levels and loss of transfusion dependence, with hardly any side effects. A phase 3 trial to compare luspatercept to ESAs (COMMANDS study) is ongoing.Luspatercept is a promising alternative to ESAs for a subset of transfusion-dependent patients with lower risk MDS, namely those with a sideroblastic phenotype who are either not suitable for or have already failed erythropoietin-based treatment. The favorable safety profile and convenient subcutaneous administration every 3 weeks are more conducive to patients' quality of life than chronic red blood cell transfusion therapy.

The bone marrow microenvironment (BMME) plays a key role in the pathophysiology of myelodysplastic syndromes (MDS), clonal blood disorders affecting the differentiation, and maturation of hematopoietic stem and progenitor cells (HSPCs). In lower-risk MDS patients, ineffective late-stage erythropoiesis can be restored by luspatercept, an activin receptor type IIB ligand trap. Here, we investigated whether luspatercept can modulate the functional properties of mesenchymal stromal cells (MSCs) as key components of the BMME. Luspatercept treatment inhibited Smad2/3 phosphorylation in both healthy and MDS MSCs and reversed disease-associated alterations in SDF-1 secretion. Pre-treatment of MDS MSCs with luspatercept restored the subsequent clonogenic potential of co-cultured HSPCs and increased both their stromal-adherence and their expression of both CXCR4 and ß3 integrin. Luspatercept pre-treatment of MSCs also increased the subsequent homing of co-cultured HSPCs in zebrafish embryos. MSCs derived from patients who had received luspatercept treatment had an increased capacity to maintain the colony forming potential of normal but not MDS HSPCs. These data provide the first evidence that luspatercept impacts the BMME directly, leading to a selective restoration of the ineffective hematopoiesis that is a hallmark of MDS.

Myelodysplastic syndromes (MDS) represent a heterogeneous group of myeloid neoplasms that are characterized by ineffective hematopoiesis, variable cytopenias, and a risk of progression to acute myeloid leukemia. Most patients with MDS are affected by anemia and anemia-related symptoms, which negatively impact their quality of life. While many patients with MDS have lower-risk disease and are managed by existing treatments, there currently is no clear standard of care for many patients. For patients with higher-risk disease, the treatment priority is changing the natural history of the disease by delaying disease progression to acute myeloid leukemia and improving overall survival. However, existing treatments for MDS are generally not curative and many patients experience relapse or resistance to first-line treatment. Thus, there remains an unmet need for new, more effective but tolerable strategies to manage MDS. Recent advances in molecular diagnostics have improved our understanding of the pathogenesis of MDS, and it is becoming clear that the diverse nature of genetic abnormalities that drive MDS demands a complex and personalized treatment approach. This review will discuss some of the challenges related to the current MDS treatment landscape, as well as new approaches currently in development.

Myelodysplastic syndromes (MDS) encompass a variety of myeloid neoplasms characterized by ineffective hematopoiesis. The interaction of abnormal clonal hematopoiesis and changes in the bone marrow microenvironment propagate abnormal clones. Advances in next generation sequencing has identified over 100 somatic mutations, but despite deepened understanding of the genetics of MDS, therapeutic discoveries have remained limited. To date, only five drugs have been approved for MDS: Azacitidine, Decitabine, Lenalidomide, Luspatercept, and oral Decitabine with Cedazuridine. Current strategies for low-risk MDS continue to focus on symptomatic management and correction of cytopenias, while treatment for high-risk MDS focuses on delaying progression of disease and improving survival. In this review we discuss some of the challenges in developing pre-clinical models of MDS in which to test therapeutics, the advances that have been made, and promising novel therapeutics in the pipeline.

Myelodysplastic syndrome (MDS) refers to a heterogeneous group of clonal blood disorders characterized by ineffective hematopoiesis, cytopenia, dysplasia, and an increased risk of acute myeloid leukemia (AML). A growing number of inherited genetic loci that contribute to MDS/AML development are rapidly being identified. As genetic sequencing has become increasingly integrated into clinical practice, clearly defined syndromes have emerged, known as the MDS/AML predisposition syndrome. With more patients and families being identified with predisposing conditions, knowledge of the approach of evaluating and managing MDS with genetic predisposition is increasingly essential. This article reviews MDS with genetic predisposition and the practical aspects of management in patients with predisposition syndrome.

This study was conducted to determine the dosage effect of c-Myc on hematopoiesis and its distinct role in mediating the Wnt/β-catenin pathway in hematopoietic stem cell (HSC) and bone marrow niche cells. c-Myc haploinsufficiency led to ineffective hematopoiesis by inhibiting HSC self-renewal and quiescence and by promoting apoptosis. We have identified Nr4a1, Nr4a2, and Jmjd3, which are critical for the maintenance of HSC functions, as previously unrecognized downstream targets of c-Myc in HSCs. c-Myc directly binds to the promoter regions of Nr4a1, Nr4a2, and Jmjd3 and regulates their expression. Our results revealed that Nr4a1 and Nr4a2 mediates the function of c-Myc in regulating HSC quiescence, whereas all 3 genes contribute to the function of c-Myc in the maintenance of HSC survival. Adenomatous polyposis coli (Apc) is a negative regulator of the Wnt/β-catenin pathway. We have provided the first evidence that Apc haploinsufficiency induces a blockage of erythroid lineage differentiation through promoting secretion of IL6 in bone marrow endothelial cells. We found that c-Myc haploinsufficiency failed to rescue defective function of Apc-deficient HSCs in vivo but it was sufficient to prevent the development of severe anemia in Apc–heterozygous mice and to significantly prolong the survival of those mice. Furthermore, we showed that c-Myc–mediated Apc loss induced IL6 secretion in endothelial cells, and c-Myc haploinsufficiency reversed the negative effect of Apc-deficient endothelial cells on erythroid cell differentiation. Our studies indicate that c-Myc has a context-dependent role in mediating the function of Apc in hematopoiesis.

Este artículo se encuentra disponible en la siguiente URL: https://actavetscand.biomedcentral.com/track/pdf/10.1186/s13028-021-00573-3.pdf Myeloid disorders are conditions being characterized by abnormal proliferation and development of myeloid lineage including granulocytes (neutrophils, eosinophils and basophils), monocytes, erythroids, and megakaryocytes precursor cells. Myeloid leukemia, based on clinical presentation and proliferative rate of neoplastic cells, is divided into acute (AML) and myeloproliferative neoplasms (MPN). The most commonly myeloid leukemia reported in horses are AML-M4 (myelomonocytic) and AML-M5 (monocytic). Isolated cases of AML-M6B (acute erythroid leukemia), and chronic granulocytic leukemia have also been reported. Additionally, bone marrow disorders with dysplastic alterations and ineffective hematopoiesis affecting single or multiple cell lineages or myelodysplastic diseases (MDS), have also been reported in horses. MDSs have increased myeloblasts numbers in blood or bone marrow, although less than 20%, which is the minimum level required for diagnosis of AML. This review performed a detailed description of the current state of knowlegde of the myeloproliferative disorders in horses following the criteria established by the World Health Organization.

Introduction Myelodysplastic syndromes (MDS) represent a heterogeneous group of malignant stem cell neoplasms hallmarked by ineffective hematopoiesis and risk of leukemic transformation. Advancements in genomic techniques such as next generation sequencing (NGS) have dramatically enhanced our knowledge of the underlying genetic alterations in MDS. Of all somatic mutations identified in MDS, TP53 mutations are associated with the most inferior outcomes across independent studies with a median OS of 6–12 months.1,2Additionally, TP53 mutations predict for inferior OS to hypomethylating agents, as well as allogeneic stem cell transplantation, which are the only disease modifying therapies.3–7 Together, these data highlight the profound negative connotation of TP53 mutation in MDS and the urgent need for effective, biologically rational, targeted therapies.

TPS7055 Background: MDS is a clonal myeloid disorder characterized by cytopenia and ineffective hematopoiesis. The median age of diagnosis is approximately 70 yrs of age and prognosis and treatment are guided by the Revised International Prognostic Scoring System (IPSS-R) criteria. Patients with intermediate, high and very high risk MDS (HR-MDS) have a median overall survival (OS) of 0.8 to 3.7 years. Despite the high unmet need in this patient population, azacitidine (AZA) is the only approved therapy for HR-MDS which has improved overall survival in clinical trials to date. However, these agents lead to low complete response (CR) rates (10-17%) with limited OS ( = 2 years), indicating a need for alternative therapy. Magrolimab is a first-in-class monoclonal antibody that blocks the macrophage inhibitory immune checkpoint CD47, a “do not eat me” signal overexpressed on tumor cells. Binding of magrolimab to CD47 leads to phagocytosis of tumor cells. AZA increases expression of prophagocytic “eat me” signals, facilitating synergy with magrolimab. In an ongoing phase 1b study, the combination of magrolimab + AZA led to high response rates (ORR 91%, with a CR of 42%) and an acceptable safety profile without significant immune-related adverse events. ENHANCE (NCT04313881) is a phase 3 trial comparing the efficacy and safety of magrolimab + AZA with that of AZA + placebo (PBO) in previously untreated patients with HR-MDS. Methods: Patients ≥18 years old with previously untreated intermediate to very high risk MDS by IPSS-R are eligible for ENHANCE. Randomization is 1:1 to magrolimab + AZA or AZA + PBO with no crossover allowed. Magrolimab or placebo is administered intravenously (IV) with an initial 1 mg/kg priming dose to mitigate on target anemia. An intrapatient dose escalation regimen up to 30 mg/kg is then administered through Cycle 1, 30 mg/kg weekly dosing in Cycle 2, with 30 mg/kg Q2W dosing occurring in Cycle 3 and beyond. AZA is administered per regional prescribing information. Patients may remain on treatment until disease progression, relapse, loss of clinical benefit, or until unacceptable toxicities occur. Two primary efficacy endpoints are CR rate and OS. For patients undergoing allogeneic stem cell transplantation (ASCT), data for the CR rate will be censored at the time of ASCT and OS will be censored at the last known alive date. Secondary efficacy endpoints include RBC transfusion independence rate, event-free survival, minimal residual disease-negative rate, time to AML transformation, and patient-reported Functional Assessment of Cancer Therapy (FACT)-Anemia response rate. Biomarkers of immune cell recruitment, immune cell signaling, and bone marrow penetration of magrolimab will also be explored. Planned enrollment is approximately 520 patients globally, which began in September 2020. Accrual is ongoing. Clinical trial information: NCT04313881.

Myelodysplastic syndromes are hematological malignancies characterized by ineffective hematopoiesis and a high risk of progression to acute myeloid leukemia. Hypomethylating agents (HMAs), azacitidine and decitabine, are standard of care therapy for higher-risk myelodysplastic syndromes. However, outcomes reported for real-world studies fall short of those achieved in clinical trials. We conducted a targeted literature review exploring real-world utilization, persistence and outcomes with intravenous and subcutaneous HMA therapies to better understand barriers to achieving optimal outcomes in clinical practice. The potential benefits of oral HMA therapy were also explored. Underutilization and poor persistence with HMA therapy are associated with suboptimal outcomes, highlighting the need for approaches to improve utilization and persistence, so that patients achieve the optimum benefit from HMA therapy.Lay abstract Myelodysplastic syndromes (MDS) are bone marrow disorders affecting the production of blood cells. In some patients, MDS can progress to acute myeloid leukemia (AML), an aggressive blood cancer with poor prognosis. Patients with higher-risk MDS are often treated with a type of chemotherapy called hypomethylating agents (HMAs). Studies conducted in real-world clinical practice have shown HMAs to be less effective than has been found in clinical trials. We reviewed available studies exploring real-world utilization, persistence and outcomes with current HMA therapies to better understand any barriers to patients achieving the best outcomes. Two important factors were found to be the underuse of HMAs and poor persistence with HMA therapy, highlighting the need for approaches to improve HMA utilization and persistence.

Myelodysplastic syndromes (MDS) are acquired clonal stem cell disorders exhibiting ineffective hematopoiesis, dysplastic cell morphology in the bone marrow, and peripheral cytopenia at early stages; while advanced stages carry a high risk for transformation into acute myeloid leukemia (AML). Genetic alterations are integral to the pathogenesis of MDS. However, it remains unclear how these genetic changes in hematopoietic stem and progenitor cells (HSPCs) occur, and how they confer an expansion advantage to the clones carrying them. Recently, inflammatory processes and changes in cellular metabolism of HSPCs and the surrounding bone marrow microenvironment have been associated with an age-related dysfunction of HSPCs and the emergence of genetic aberrations related to clonal hematopoiesis of indeterminate potential (CHIP). The present review highlights the involvement of metabolic and inflammatory pathways in the regulation of HSPC and niche cell function in MDS in comparison to healthy state and discusses how such pathways may be amenable to therapeutic interventions.

Introduction Inherited bone marrow failure syndromes (IBMFS) feature complex molecular pathophysiology resulting in ineffective hematopoiesis and increased risk of progression to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Allogenic hematopoietic stem cell transplantation (HSCT) is the only well-established cure for the hematological manifestations of these diseases. Areas covered In recent years, analysis of large series from international databases (mainly from the European Bone Marrow Transplantation [EBMT] database) has improved knowledge about HSCT in IBMFS. This review, following a thorough Medline search of the pertinent published studies, reports the most recent data on HSCT in IBMFS. Expert opinion Despite the common features, IBMFS are very different in their manifestations and in the occurrence and management of HSCT complications. Thus, a "disease-specific" HSCT using an optimized conditioning regimen based on the characteristics of the disease is essential for achieving long-term survival. The phenotypical heterogeneity associated with extramedullary abnormalities has to be carefully evaluated before HSCT because transplantation may only correct impaired hematopoiesis. HSCT may be associated with the risk of treatment-related mortality and with significant early and late morbidity. For these reasons, the benefits should be carefully weighed against the risks.

Chronic Granulomatous Disease (CGD) is an inborn error of immunity characterized by impaired phagocyte function, recurrent fungal and bacterial infections and granuloma formation in multiple organs. Pediatric myelodysplastic Syndrome (MDS) is a rare hematological stem cell disease that leads to an ineffective hematopoiesis with variable risk of evolution to acute leukemias. Both disorders are rare and have distinct pathophysiologic mechanisms, with no known association. A 7-month-old boy presenting with recurrent infections and anemia at age 2 months underwent immunological, hematological and genetic investigation that culminated in the diagnosis of both CGD and MDS. Next generation sequencing was performed and identified a silent variant predicted as of Uncertain Significance, located in the splicing site at the end of exon 5 in CYBB. CYBB variants account for at least two thirds of CGD cases, but no previous descriptions of this variant were found in ClinVar or The Human Gene Mutation Database (HGMD) databases. We were able to demonstrate an exon 5 skipping on the proband’s cDNA, which strongly suggests the disruption of the NADPH oxidase complex, abrogating the formation of reactive oxygen species from neutrophils. Moreover, erythroid cell lineage could be also affected by NADPH oxidase complex damages. Further investigation is needed to evaluate the potential effect of CYBB gene alterations in hematopoiesis, as well as in MDS and CGD association.

The myelodysplastic syndromes (MDS) represent a group of clonal disorders characterized by ineffective hematopoiesis, resulting in peripheral cytopenias and frequent transformation to acute myeloid leukemia (AML). We and others have demonstrated that MDS arises in, and is propagated by malignant stem cells (MDS-SCs), that arise due to the sequential acquisition of genetic and epigenetic alterations in normal hematopoietic stem cells (HSCs). This review focuses on recent advancements in the cellular and molecular characterization of MDS-SCs, as well as their role in mediating MDS clinical outcomes. In addition to discussing the cell surface proteins aberrantly upregulated on MDS-SCs that have allowed the identification and prospective isolation of MDS-SCs, we will discuss the recurrent cytogenetic abnormalities and genetic mutations present in MDS-SCs and their roles in initiating disease, including recent studies demonstrating patterns of clonal evolution and disease progression from pre-malignant HSCs to MDS-SCs. We also will discuss the pathways that have been described as drivers or promoters of disease, including hyperactivated innate immune signaling, and how the identification of these alterations in MDS-SC have led to investigations of novel therapeutic strategies to treat MDS. It is important to note that despite our increasing understanding of the pathogenesis of MDS, the molecular mechanisms that drive responses to therapy remain poorly understood, especially the mechanisms that underlie and distinguish hematologic improvement from reductions in blast burden. Ultimately, such distinctions will be required in order to determine the shared and/or unique molecular mechanisms that drive ineffective hematopoiesis, MDS-SC maintenance, and leukemic transformation.

Myelodysplastic syndromes (MDS) are a group of clonal hematopoietic neoplasms characterized by ineffective hematopoiesis and myelodysplasia with a variable spectrum of clinical–biological features that can be used to build a prognostic estimation. This review summarizes the current most widely used prognostic scoring systems and gives a general view of the prognostic impact of somatic mutations in MDS patients.

Thrombocytopenia is a major cause of morbidity and mortality in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) [1]. Ineffective hematopoiesis and infiltration of the...

Myelodysplastic syndromes (MDS) are characterized by dysplastic and ineffective hematopoiesis that can result from aberrant expansion and activation of myeloid-derived suppressor cells (MDSCs) within the bone marrow (BM) niche. MDSCs produce S100A9, which mediates premature death of hematopoietic stem and progenitor cells (HSPCs). The PD-1/PD-L1 immune checkpoint impairs immune responses by inducing T-cell exhaustion and apoptosis, but its role in MDS is uncharacterized. Here we report an increased expression of PD-1 on HSPCs and PD-L1 on MDSCs in MDS versus healthy donors, and that this checkpoint is also activated in S100A9 transgenic (S100A9Tg) mice, and by treatment of BM mononuclear cells (BM-MNC) with S100A9. Further, MDS BM-MNC treated with recombinant PD-L1 underwent cell death, suggesting that the PD-1/PD-L1 interaction contributes to HSPC death in MDS. In accordance with this notion, PD-1/PD-L1 blockade restores effective hematopoiesis and improves colony-forming capacity in BM-MNC from MDS patients. Similar findings were observed in aged S100A9Tg mice. Finally, we demonstrate that c-Myc is required for S100A9-induced upregulation of PD-1/PD-L1, and that treatment of MDS HSPCs with anti-PD-1 antibody suppresses the expression of Myc target genes and increases the expression of hematopoietic pathway genes. We conclude anti-PD-1/anti-PD-L1 blocking strategies offer therapeutic promise in MDS in restoring effective hematopoiesis.

Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis and risk of evolution to acute myeloid leukemia (AML) [1]. Presentation varies from mild cytopenia to profound symptom...

To the Editor,The myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic conditions characterized by dysplastic changes and ineffective hematopoiesis [1]. Almost all patients with...

Myelodysplastic syndromes (MDS) are a heterogeneous group of diseases characterized by ineffective hematopoiesis and a wide spectrum of manifestations ranging from indolent and asymptomatic cytopenias to acute myeloid leukemia (AML). MDS result from genetic and epigenetic derangements in clonal cells and their surrounding microenvironments. Studies have shown associations between MDS and other autoimmune diseases. Several immune mechanisms have been identified in MDS, suggesting that immune dysregulation might be at least partially implicated in its pathogenesis. This has led to rigorous investigations on the role of immunomodulatory drugs as potential treatment options. Epigenetic modification via immune check point inhibition, while well established as a treatment method for advanced solid tumors, is a new approach being considered in hematologic malignancies including high risk MDS. Several trials are looking at the efficacy of these agents in MDS, as frontline therapy and in relapse, both as monotherapy and in combination with other drugs. In this review, we explore the utility of immune checkpoint inhibitors in MDS and current research evaluating their efficacy.

Myelodysplastic syndromes (MDS) are clonal stem cell diseases characterized mainly by ineffective hematopoiesis. Here, we present an approach that enables robust long-term engraftment of primary MDS stem cells (MDS-SC) in mice by implantation of human mesenchymal cell–seeded scaffolds. Critically for modeling MDS, where patient sample material is limiting, mononuclear bone marrow cells containing as few as 104 CD34+ cells can be engrafted and expanded by this approach with the maintenance of the genetic make-up seen in the patients. Noninvasive high-resolution ultrasound imaging shows that these scaffolds are fully perfused. Our data show that the human microenvironment but not mouse is essential to MDS-SC homing and engraftment. Notably, the alternative niche provided by healthy donor mesenchymal stromal cells enhances engraftment of MDS-SCs. This study characterizes a new tool to model MDS human disease with the level of engraftment previously unattainable in mice and offers insights into human-specific determinants of the MDS-SC microenvironment. Significance: These findings are significant for understanding the niche dependence of MDS. This report provides the evidence of the migratory behavior of hematopoietic stem cells in myeloid cancers. Our model offers a unique opportunity to study the clonal behavior of the myeloid/lymphoid cancers and delineate how cancer cells interact with different niches.

Background Fetal hemoglobin (HbF) induction has shown promise for the treatment of β-hemoglobinopathies. HbF induction in β-thalassemia could overcome ineffective hematopoiesis and thus terminate transfusion dependency for formerly transfusion dependant patients. Several miRNAs have been found to reactivate γ-globin expression and increase HbF. In this study, we aimed to investigate the expression of 4 miRNAs (miR-15a, miR-16-1, miR-96, and miR-486-3p) in high HbF thalassemia patients and correlate their levels with the patients’ HbF levels then, in order to predict the exact role of the studied miRNAs in hematopoiesis, a bioinformatic analysis was carried out. We went through this bioinformatic analysis to determine the network of genes regulated by miRNAs and further investigate the interaction between all of them through their involvement in hematopoiesis. In this study, the differential expression was measured by qRT-PCR for 40 patients with high HbF and compared to 20 healthy controls. Bioinformatics was conducted involving functional annotation and pathway enrichment analyses. Results The studied microRNAs were significantly deregulated in thalassemia patients in correlation with HbF. Functional annotation and pathway enrichment analyses revealed a major role of miR-486-3p and miR-15a in HbF induction. Conclusion MiR-486-3p and miR-15a are crucial for HbF induction. Further validating studies are needed.

Simple Summary Myelodysplastic syndromes (MDS) are a group of diseases in which bone marrow stem cells acquire genetic alterations and can initiate leukemia, blocking the production of mature blood cells. It is of crucial importance to identify those genetic abnormalities because some of them can be the targeted. To date only very few drugs are approved for patients manifesting this group of disorders and there is an urgent need to develop new effective therapies. This review gives an overview of the genetic of MDS and the therapeutic options available and in clinical experimentation. Abstract Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic disorders characterized by ineffective hematopoiesis, progressive cytopenias and increased risk of transformation to acute myeloid leukemia. The improved understanding of the underlying biology and genetics of MDS has led to better disease and risk classification, paving the way for novel therapeutic opportunities. Indeed, we now have a vast pipeline of targeted agents under pre-clinical and clinical development, potentially able to modify the natural history of the diverse disease spectrum of MDS. Here, we review the latest therapeutic approaches (investigational and approved agents) for MDS treatment. A deep insight will be given to molecularly targeted therapies by reviewing new agents for individualized precision medicine.

Genetic and epigenetic lesions within hematopoietic cell populations drive diverse hematological malignancies. Myelodysplastic syndromes (MDS) are a group of myeloid neoplasms affecting the hematopoietic stem cells characterized by recurrent genetic abnormalities, myelodysplasia (a pathological definition of abnormal bone marrow structure), ineffective hematopoiesis resulting in blood cytopenia, and a propensity to evolve into acute myelogenous leukemia. Although there is evidence that the accumulation of a set of genetic mutations is an essential event in MDS, there is an increased appreciation of the contribution of specific microenvironments, niches, in the pathogenesis of MDS and response to treatment. In physiologic hematopoiesis, niches are critical functional units that maintain hematopoietic stem and progenitor cells and regulate their maturation into mature blood cells. In MDS and other hematological malignancies, altered bone marrow niches can promote the survival and expansion of mutant hematopoietic clones and provide a shield from therapy. In this review, we focus on our understanding of the composition and function of hematopoietic niches and their role in the evolution of myeloid malignancies, with an emphasis on MDS.

Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell (HSC) malignancies characterized by ineffective hematopoiesis with increased incidence in elderly individuals. Genetic alterations do not fully explain the molecular pathogenesis of the disease, indicating that other types of lesions may play a role in its development. In this work, we analyzed the transcriptional lesions of human HSCs, demonstrating how aging and MDS are characterized by a complex transcriptional rewiring that manifests as diverse linear and non-linear transcriptional dynamisms. While aging-associated lesions seemed to predispose elderly HSCs to myeloid transformation, disease-specific alterations may be involved in triggering MDS development. Among MDS-specific lesions, we detected the overexpression of the transcription factor DDIT3. Exogenous upregulation of DDIT3 in human healthy HSCs induced an MDS-like transcriptional state, and a delay in erythropoiesis, with an accumulation of cells in early stages of erythroid differentiation, as determined by single-cell RNA-sequencing. Increased DDIT3 expression was associated with downregulation of transcription factors required for normal erythropoiesis, such as KLF1, TAL1 or SOX6, and with a failure in the activation of their erythroid transcriptional programs. Finally, DDIT3 knockdown in CD34+ cells from MDS patients was able to restore erythropoiesis, as demonstrated by immunophenotypic and transcriptional profiling. These results demonstrate that DDIT3 may be a driver of MDS transformation, and a potential therapeutic target to restore the inefficient erythropoiesis characterizing these patients. KEY POINTSO_LIHuman HSCs undergo a complex transcriptional rewiring in aging and MDS that may contribute to myeloid transformation. C_LIO_LIDDIT3 overexpression induces a failure in the activation of erythroid transcriptional programs, leading to inefficient erythropoiesis. C_LI

Myelodysplastic syndrome (MDS) is a heterogeneous hematological neoplasm with a wide range of clinical presentations from isolated anemia to pancytopenia and propensity to transform to acute myeloid leukemia. MDS is characterized by morphologic bone marrow dysplasia and ineffective hematopoiesis resulting from a range of cytogenetic abnormalities and somatic gene mutations. Disease management varies from observation alone for low-risk disease to hypomethylating agents and hematopoietic cell transplantation (HCT) for higher risk disease. In this chapter, we review the classification, risk stratification, and optimal management of patients with MDS.

Myelodysplastic Syndromes (MDS) are a heterogeneous group of clonal stem cell disorders that predominantly affect the elderly. They are characterized by ineffective hematopoiesis, peripheral blood cytopenias and an increased risk of developing acute myeloid leukemia. Chronic inflammation plays a crucial role in MDS pathogenesis and progression. Mounting evidence has been suggesting the potential diagnostic/prognostic value of circulating microRNAs (miRNAs) – short non-coding RNAs that are capable of modulating gene expression – in MDS and other hematologic malignancies. In this study, the serum expression of 14 miRNAs involved in the modulation of inflammation (inflamma-miRs) was determined in 68 MDS patients and 68 age-matched healthy donors to identify those having diagnostic/prognostic value. Compared to the healthy donors, patients had significantly lower miR-155 and miR-181a and significantly higher miR-19b levels. When patients were grouped according to the International Prognostic Scoring System (IPSS), those at lower risk showed significantly lower miR-21, -146a, -155, and -181a levels and significantly higher miR-19b levels. Notably, 2-year overall survival probability was significantly lower in patients with higher miR-21, -155, and -181a. Altogether, our data suggest that an MDS-specific circulating inflamma-miR signature could provide an innovative, non-invasive diagnostic and prognostic biomarker of these disorders.

Hematopoietic elements identified outside of the bone marrow are defined as extramedullary hematopoiesis (EMH) and is observed normally during embryonic development and fetal life. Conditions secondary to insufficient bone marrow function or ineffective hematopoiesis, malignancies, as well as stromal disorders of the bone maylead to EMH in adult liver, spleen and lymph nodes. EMH in the adrenal is rare, with very few cases reported. We present a case series of five patients, of which two presented with non-specific complaints and three were found to have an incidental abdominal mass on radiology. These were reported as EMH of adrenal gland on histology. None of our five cases had any underlying disease making the present case series interesting and unique.

Myelodysplastic syndromes are a group of clonal diseases of hematopoietic stem cells and are characterized by multilineage dysplasia, ineffective hematopoiesis, peripheral blood cytopenias, genetic instability and a risk of transformation to acute myeloid leukemia. Some patients with non-Hodgkin lymphomas (NHLs) may have developed secondary myelodysplasia before therapy. Bone marrow (BM) hematopoiesis is regulated by a spectrum of epigenetic factors, among which microRNAs (miRNAs) are special. The aim of this work is to profile miRNA expression in BM cells in untreated NHL patients with secondary myelodysplasia. A comparative analysis of miRNA expression levels between the NHL and non-cancer blood disorders samples revealed that let-7a-5p was upregulated, and miR-26a-5p, miR-199b-5p, miR-145-5p and miR-150-5p were downregulated in NHL with myelodysplasia (p &lt, 0.05). We for the first time developed a profile of miRNA expression in BM samples in untreated NHL patients with secondary myelodysplasia. It can be assumed that the differential diagnosis for blood cancers and secondary BM conditions based on miRNA expression profiles will improve the accuracy and relevance of the early diagnosis of cancerous and precancerous lesions in BM.

Inherited bone marrow failure syndromes (IBMFSs) are characterized by ineffective hematopoiesis and increased risk for developing myeloid malignancy. The pathophysiologies of different IBMFSs are variable and can relate to defects in diverse biological processes, including DNA damage repair (Fanconi anemia), telomere maintenance (dyskeratosis congenita), and ribosome biogenesis (Diamond-Blackfan anemia, Shwachman-Diamond syndrome). Somatic mutations leading to clonal hematopoiesis have been described in IBMFSs, but the distinct mechanisms by which mutations drive clonal advantage in each disease and their associations with leukemia risk are not well understood. Clinical observations and laboratory models of IBMFSs suggest that the germline deficiencies establish a qualitatively impaired functional state at baseline. In this context, somatic alterations can promote clonal hematopoiesis by improving the competitive fitness of specific hematopoietic stem cell clones. Some somatic alterations relieve baseline fitness constraints by normalizing the underlying germline deficit through direct reversion or indirect compensation, whereas others do so by subverting senescence or tumor-suppressor pathways. Clones with normalizing somatic mutations may have limited transformation potential that is due to retention of functionally intact fitness-sensing and tumor-suppressor pathways, whereas those with mutations that impair cellular elimination may have increased risk for malignant transformation that is due to subversion of tumor-suppressor pathways. Because clonal hematopoiesis is not deterministic of malignant transformation, rational surveillance strategies will depend on the ability to prospectively identify specific clones with increased leukemic potential. We describe a framework by which an understanding of the processes that promote clonal hematopoiesis in IBMFSs may inform clinical surveillance strategies.

Myelodysplastic syndromes (MDS) are a heterogeneous group of malignant disorders of hematopoietic stem and progenitor cells (HSPC), mainly characterized by ineffective hematopoiesis leading to peripheral cytopenias and progressive bone marrow failure. While clonal dominance is nearly universal at diagnosis, most genetic mutations identified in patients with MDS do not provide a conspicuous advantage to the malignant cells. In this context, malignant cells alter their adjacent bone marrow microenvironment (BME) and rely on cell extrinsic factors to maintain clonal dominance. The profoundly disturbed BME favors the myelodysplastic cells and, most importantly is detrimental to normal hematopoietic cells. Thus, the MDS microenvironment not only contributes to the observed cytopenias seen in these patients but could also negatively impact the engraftment of normal, allogeneic HSPCs in patients with MDS undergoing bone marrow transplant. Therefore, successful therapies in MDS should not only target the malignant cells but also reprogram their bone marrow microenvironment. Here, we will provide a synopsis of how drugs currently used or on the verge of being approved for the treatment of MDS may achieve this goal.

There is growing interest in the contribution of the marrow niche to the pathogenesis of bone marrow failure syndromes, i.e., aplastic anemia (AA) and myelodysplastic syndromes (MDSs). In particular, mesenchymal stem cells (MSCs) are multipotent cells that contribute to the organization and function of the hematopoietic niche through their repopulating and supporting abilities, as well as immunomodulatory properties. The latter are of great interest in MDSs and, particularly, AA, where an immune attack against hematopoietic stem cells is the key pathogenic player. We, therefore, conducted Medline research, including all available evidence from the last 10 years concerning the role of MSCs in these two diseases. The data presented show that MSCs display morphologic, functional, and genetic alterations in AA and MDSs and contribute to immune imbalance, ineffective hematopoiesis, and leukemic evolution. Importantly, adoptive MSC infusion from healthy donors can be exploited to heal the “sick” niche, with even better outcomes if cotransplanted with allogeneic hematopoietic stem cells. Finally, future studies on MSCs and the whole microenvironment will further elucidate AA and MDS pathogenesis and possibly improve treatment.

The myelodysplastic syndromes (MDS) are a heterogeneous constellation of hematologic malignancies characterized by aberrant differentiation and clonal expansion of abnormal myeloid cells that initially manifest with ineffective hematopoiesis and consequent cytopenias. The prognosis of MDS is variable and depends on clinical and hematologic parameters, cytogenetic and molecular findings, as well as comorbidities. Gene sequencing studies have uncovered remarkable genomic complexity within MDS, based on the presence of recurrent and sometimes co-operating mutations in genes encoding proteins that play a role in numerous biologic pathways. Although the treatment of MDS is currently limited to the use of hypomethylating, immunomodulatory, or erythropoiesis-stimulating agents, improved understanding of the molecular underpinnings of its pathophysiology has led to the development of multiple targeted treatments that are poised to be added to the therapeutic armamentarium. This review will focus on the role of mutations in the pathogenesis, diagnosis, and prognosis of MDS and how the discovery of clonal hematopoiesis of indeterminate potential (CHIP) might impact the utility of detecting mutations in the diagnosis of MDS.

Myelodysplastic syndrome (MDS) represents a heterogeneous group of clonal hematopoietic disorders, which is characterized by cytopenias in the peripheral blood and bone marrow dysplasia due to ineffective hematopoiesis. Patients with MDS have an increased risk of transformation to acute myeloid leukemia (AML). Although the molecular basis of MDS is heterogeneous, several studies demonstrated the significant contribution of the dysregulated immune system in accelerating MDS progression. The immunosuppressive tumor microenvironment is shown to induce tolerance of MDS blasts, which may result in a further accumulation of genetic aberrations and lead to the disease progression. Increasing evidence shows an expansion of myeloid-derived suppressor cells (MDSCs), a population of inflammation-associated immature cells, in patients with MDS. Interestingly, the increased MDSC populations are shown to be correlated with a risk of disease progression in MDS. In addition, MDS is highly prevalent in aged individuals with non-hematology co-morbidities who are fragile for chemotherapy. Increasing research effort is devoting to identify novel agents to specific targeting of the MDSC population for MDS treatment.

Myelofibrosis (MF), either appearing de novo (primary MF, PMF) or after a previous diagnosis of essential thrombocythemia or of polycythemia vera, is a progressive disease burdened by symptomatic splenomegaly, debilitating systemic symptoms, ineffective hematopoiesis, and overall reduced survival. Patients often present worsening cytopenias, including thrombocytopenia, secondary to progression of the disease as well as to cytoreductive treatment. Patients with MF and thrombocytopenia have few therapeutic options and there is limited information regarding the management of disease in these settings. This article reviews current evidence for the management of patients with MF and thrombocytopenia, in the era of JAK inhibitors.

Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis and often include a dysregulation and dysfunction of the immune system. In the context of population aging, MDS incidence is set to increase substantially, with exponential increases in health care costs, given the limited and expensive treatment options for these patients. Treatment selection is mainly based on calculated risk categories according to a Revised International Prognostic Scoring System (IPSS-R). However, although IPSS-R is an excellent predictor of disease progression, it is an ineffective predictor of response to disease-modifying therapies. Redressing these unmet needs, the “immunome” is a key, multifaceted component in the initiation and overall response against malignant cells in MDS, and the current omission of immune status monitoring may in part explain the insufficiencies of current prognostic stratification methods. Nevertheless, integrating these and other recent molecular advances into clinical practice proves difficult. This review highlights the complexity of immune dysregulation in MDS pathophysiology and the fine balance between smoldering inflammation, adaptive immunity, and somatic mutations in promoting or suppressing malignant clones. We review the existing knowledge and discuss how state-of-the-art immune monitoring strategies could potentially permit novel patient substratification, thereby empowering practical predictions of response to treatment in MDS. We propose novel multicenter studies, which are needed to achieve this goal.

Myelodysplastic syndromes (MDS) are clonal malignant hematopoietic disorders in the elderly characterized by ineffective hematopoiesis. This is accompanied by an altered bone microenvironment, which contributes to MDS progression and higher bone fragility. The underlying mechanisms remain largely unexplored. Here, we show that myelodysplastic NUP98‑HOXD13 (NHD13) transgenic mice display an abnormally high number of osteoblasts, yet a higher fraction of nonmineralized bone, indicating delayed bone mineralization. This was accompanied by high fibroblast growth factor-23 (FGF-23) serum levels, a phosphaturic hormone that inhibits bone mineralization and erythropoiesis. While Fgf23 mRNA expression was low in bone, brain, and kidney of NHD13 mice, its expression was increased in erythroid precursors. Coculturing these precursors with WT osteoblasts induced osteoblast marker gene expression, which was inhibited by blocking FGF-23. Finally, antibody-based neutralization of FGF-23 in myelodysplastic NHD13 mice improved bone mineralization and bone microarchitecture, and it ameliorated anemia. Importantly, higher serum levels of FGF‑23 and an elevated amount of nonmineralized bone in patients with MDS validated the findings. C‑terminal FGF‑23 correlated negatively with hemoglobin levels and positively with the amount of nonmineralized bone. Thus, our study identifies FGF-23 as a link between altered bone structure and ineffective erythropoiesis in MDS with the prospects of a targeted therapeutic intervention.

Signaling by the TGF-β superfamily is important in the regulation of hematopoiesis and is dysregulated in myelodysplastic syndromes (MDSs), contributing to ineffective hematopoiesis and clinical cytopenias. TGF-β, activins, and growth differentiation factors exert inhibitory effects on red cell formation by activating canonical SMAD2/3 pathway signaling. In this Review, we summarize evidence that overactivation of SMAD2/3 signaling pathways in MDSs causes anemia due to impaired erythroid maturation. We also describe the basis for biological activity of activin receptor ligand traps, novel fusion proteins such as luspatercept that are promising as erythroid maturation agents to alleviate anemia and related comorbidities in MDSs and other conditions characterized by impaired erythroid maturation.