Search Results (14)

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematological malignancies characterized by ineffective hematopoiesis, resulting in cytopenias, morphologic dysplasia in hematopoietic lineages, and a variable risk of progression to acute myeloid leukemia. Significant advances in the understanding of MDS have been made in recent years, largely due to the implementation of molecular tools. Latin America is a highly diverse region, both ethnically and racially, and often faces resource limitations that challenge the broad applicability of recent advances in MDS. In this review, we discuss the key genes implicated in the pathogenesis and classification of MDS, and their relevance to diagnosis, prognosis, and potential therapeutic targets. We also explore the challenges associated with the identification of germline predisposition to MDS in Latin America and discuss the current availability and limitations of molecular diagnostic tools in the region. Full article

Clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing has begun to transform the treatment landscape of genetic diseases. The history of the discovery of CRISPR/CRISPR-associated (Cas) proteins/single-guide RNA (sgRNA)-based gene editing since the first report of repetitive sequences of unknown significance in 1987 is fascinating, highly instructive, and inspiring for future advances in medicine. The recent approval of CRISPR-Cas9-based gene therapy to treat patients with severe sickle cell anemia and transfusion-dependent β-thalassemia has renewed hope for treating other hematologic diseases, including patients with a germline predisposition to hematologic malignancies, who would benefit greatly from the development of CRISPR-inspired gene therapies. The purpose of this paper is three-fold: first, a chronological description of the history of CRISPR-Cas9-sgRNA-based gene editing; second, a brief description of the current state of clinical research in hematologic diseases, including selected applications in treating hematologic diseases with CRISPR-based gene therapy, preceded by a brief description of the current tools being used in clinical genome editing; and third, a presentation of the current progress in gene therapies in inherited hematologic diseases and bone marrow failure syndromes, to hopefully stimulate efforts towards developing these therapies for patients with inherited bone marrow failure syndromes and other inherited conditions with a germline predisposition to hematologic malignancies. Full article

Myelodysplastic neoplasm (MDS) is a heterogeneous group of clonal hematological disorders that originate from the hematopoietic and progenitor cells and present with cytopenias and morphologic dysplasia with a propensity to progress to bone marrow failure or acute myeloid leukemia (AML). Genetic evolution plays a critical role in the pathogenesis, progression, and clinical outcomes of MDS. This process involves the acquisition of genetic mutations in stem cells that confer a selective growth advantage, leading to clonal expansion and the eventual development of MDS. With the advent of next-generation sequencing (NGS) assays, an increasing number of molecular aberrations have been discovered in recent years. The knowledge of molecular events in MDS has led to an improved understanding of the disease process, including the evolution of the disease and prognosis, and has paved the way for targeted therapy. The 2022 World Health Organization (WHO) Classification and the International Consensus Classification (ICC) have incorporated the molecular signature into the classification system for MDS. In addition, specific germline mutations are associated with MDS development, especially in pediatrics and young adults. This article reviews the genetic abnormalities of MDS in adults with a brief review of germline predisposition syndromes. Full article

There are a variety of rare hematologic malignancies and germline predispositions syndromes that occur in children and adolescent young adults (AYAs). These entities are important to recognize, as an accurate diagnosis is essential for risk assessment, prognostication, and treatment. This descriptive review summarizes rare hematologic malignancies, myelodysplastic neoplasms, and germline predispositions syndromes that occur in children and AYAs. We discuss the unique biology, characteristic genomic aberrations, rare presentations, diagnostic challenges, novel treatments, and outcomes associated with these rare entities. Full article

Due to the proliferation of genetic testing, pathogenic germline variants predisposing to hereditary hematological malignancy syndrome (HHMS) have been identified in an increasing number of genes. Consequently, the field of HHMS is gaining recognition among clinicians and scientists worldwide. Patients with germline genetic abnormalities often have poor outcomes and are candidates for allogeneic hematopoietic stem cell transplantation (HSCT). However, HSCT using blood from a related donor should be carefully considered because of the risk that the patient may inherit a pathogenic variant. At present, we now face the challenge of incorporating these advances into clinical practice for patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) and optimizing the management and surveillance of patients and asymptomatic carriers, with the limitation that evidence-based guidelines are often inadequate. The 2016 revision of the WHO classification added a new section on myeloid malignant neoplasms, including MDS and AML with germline predisposition. The main syndromes can be classified into three groups. Those without pre-existing disease or organ dysfunction; DDX41, TP53, CEBPA, those with pre-existing platelet disorders; ANKRD26, ETV6, RUNX1, and those with other organ dysfunctions; SAMD9/SAMD9L, GATA2, and inherited bone marrow failure syndromes. In this review, we will outline the role of the genes involved in HHMS in order to clarify our understanding of HHMS. Full article

Myelodysplastic neoplasm (MDS) is a heterogeneous group of myeloid neoplasms affected by germline and somatic genetic alterations. The incidence of MDS increases with age but rarely occurs at a young age. We investigated the germline and somatic genetic alterations of Korean patients with young-onset MDS (<40 years). Among the thirty-one patients, five (16.1%) had causative germline variants predisposing them to myeloid neoplasms (three with GATA2 variants and one each with PGM3 and ETV variants). We found that PGM3 deficiency, a subtype of severe immunodeficiency, predisposes patients to MDS. Somatic mutations were identified in 14 patients (45.2%), with lower rates in patients aged < 20 years (11.1%). Nine (29%) patients had U2AF1 S34F/Y mutations, and patients with U2AF1 mutations showed significantly worse progression-free survival (p < 0.001) and overall survival (p = 0.006) than those without U2AF1 mutations. A UBA1 M41T mutation that causes VEXAS syndrome was identified in a male patient. In conclusion, a germline predisposition to myeloid neoplasms occurred in ~16% of young-onset MDS patients and was largely associated with primary immunodeficiencies, including GATA2 deficiency. Furthermore, the high frequency of somatic U2AF1 mutations in patients with young-onset MDS suggests the presence of a distinct MDS subtype. Full article

Next-generation sequencing (NGS) tools have importantly helped the classification of myelodysplastic syndromes (MDS), guiding the management of patients. However, new concerns are under debate regarding their implementation in routine clinical practice for the identification of germline predisposition. Cost-effective targeted NGS tools would improve the current standardized studies and genetic counseling. Here, we present our experience in a preliminary study detecting variants using a two-time multiplexed library strategy. Samples from different MDS patients were first mixed before library preparation and later multiplexed for a sequencing run. Two different mixes including a pool of three (3×) and four (4×) samples were evaluated. The filtered variants found in the individually sequenced samples were compared with the variants found in the two-time multiplexed studies to determine the detection efficiency scores. The same candidate variants were found in the two-time multiplexed studies in comparison with the individual tNGS. The variant allele frequency (VAF) values of the candidate variants were also compared. No significant differences were found between the expected and observed VAF percentages in both the 3× (p-value 0.74) and 4× (p-value 0.34) multiplexed studies. Our preliminary results suggest that the two-time multiplexing strategy might have the potential to help reduce the cost of evaluating germline predisposition. Full article

Classic dyskeratosis congenita is a hereditary disease where the majority of patients present with bone marrow failure and mucocutaneous changes: mainly skin pigmentation, nail dystrophy, oral premalignant leukoplakia, in addition to increased risk for malignancies. A 63-year-old man with a long history of untreated chronic pulmonary disease, a smoker in the past, presented initially with pancytopenia and a clinical diagnosis of myelodysplastic syndrome with excess blasts returned a month later with leukocytosis (WBC 215.9 × 10⁶/μL) and diagnosed with acute myeloid leukemia (AML) with deletion of chromosome 7 and FLT3-TKD mutation. The patient’s mother and sister died in their 6th decade from rapidly progressing fulminant pulmonary fibrosis. He had abnormal skin pigmentation and oral leukoplakia on presentation. He was induced with 7 + 3 chemotherapy and started on midostaurin but experienced prolonged cytopenias, complicated by hypoxic acute on chronic respiratory failure requiring intubation and mechanical ventilation. D + 28 and D + 36 bone marrow examination showed trilineage hypoplasia but no blasts, though the D + 28 bone marrow biopsy revealed one metaphase with del (7) that was cleared on D + 35. The constellation of clinical features and strong family history along with del 7 and FLT3-TKD AML with preceding MDS highly suggests a germline predisposition state dyskeratosis congenita. Germline predispositions are often underrecognized as delayed onset conditions leading to AML and may have treatment and preventative implications especially genetic counseling for blood-related family members. Full article

A suitable diagnostic classification of myeloid neoplasms and acute leukemias requires testing for a large number of molecular biomarkers. Next-generation sequencing is a technology able to integrate identification of the vast majority of them in a single test. This manuscript includes the design, analytical validation and clinical feasibility evaluation of a molecular diagnostic kit for onco-hematological diseases. It is based on sequencing of the coding regions of 76 genes (seeking single-nucleotide variants, small insertions or deletions and CNVs), as well as the search for fusions in 27 target genes. The kit has also been designed to detect large CNVs throughout the genome by including specific probes and employing a custom bioinformatics approach. The analytical and clinical feasibility validation of the Haematology OncoKitDx panel has been carried out from the sequencing of 170 patient samples from 6 hospitals (in addition to the use of commercial reference samples). The analytical validation showed sensitivity and specificity close to 100% for all the parameters evaluated, with a detection limit of 2% for SNVs and SVs, and 20% for CNVs. Clinically relevant mutations were detected in 94% of all patients. An analysis of the correlation between the genetic risk classification of AML (according to ELN 2017) established by the hospitals and that obtained by the Haematology OncoKitDx panel showed an almost perfect correlation (K = 0.94). Among the AML samples with a molecular diagnosis, established by the centers according to the WHO, the Haematology OncoKitDx analysis showed the same result in 97% of them. The panel was able to adequately differentiate between MPN subtypes and also detected alterations that modified the diagnosis (FIP1L1-PDGFRA). Likewise, the cytogenetic risk derived from the CNV plot generated by the NGS panel correlated substantially with the results of the conventional karyotype (K = 0.71) among MDS samples. In addition, the panel detected the main biomarkers of prognostic value among patients with ALL. This validated solution enables a reliable analysis of a large number of molecular biomarkers from a DNA sample in a single assay. Full article

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. Knowledge of the regulation of the germline genes and their interactions with other genes, proteins, and the environment, the penetrance and clinical presentation of inherited mutations, and the longitudinal dynamics during the process of disease progression offer models and tools that can further our understanding of myeloid neoplasms. This knowledge will eventually translate to improved disease sub-classification, risk assessment, and development of more effective therapy. In this review, we will use examples of these disorders to illustrate the key molecular pathways of myeloid neoplasms. Full article

Myelodysplastic syndromes affect an older age group with a median age at onset in the eighth decade of life. As such, there is a relationship between the pathogenesis of MDS and age-related processes affecting haematopoietic stem/progenitor cells and/or the bone marrow microenvironment. MDS with an onset in younger people may be associated with recognised hereditary myeloid malignancy syndromes, and ‘forme fruste’ presentations of inherited syndromes in later life are now increasingly recognised such as germline mutations in DDX41. The considerable clinical and research interest in hereditary disorders is reflected in the relative emphasis within our manuscript. Prior chemo/radiotherapy is a clear cause of MDS but the predisposition factors for therapy-related MDS remain unclear. Clonal haematopoiesis is common in older people and may evolve to MDS, although once again, the biological factors driving this evolution are largely unknown. Finally, environmental exposure to genotoxic agents is likely to play only a minor role in the contemporary occupational/recreational setting. Full article

Myelodysplastic syndrome (MDS) describes a heterogeneous group of bone marrow diseases, now understood to reflect numerous germline and somatic drivers, characterized by recurrent cytogenetic abnormalities and gene mutations. Precursor conditions including clonal hematopoiesis of indeterminate potential and clonal cytopenia of undetermined significance confer risk for MDS as well as other hematopoietic malignancies and cardiovascular complications. The future is likely to bring an understanding of those individuals who are at the highest risk of progression to MDS and preventive strategies to prevent malignant transformation. Full article

The impact on health care of patients with myelodysplastic syndromes (MDS) is continuously rising. To investigate the perception of hemato-oncologists concerning the recommended MDS patient care in Switzerland, we conducted a web-based survey on diagnosis, risk-stratification and treatment. 43/309 physicians (13.9%) replied to 135 questions that were based on current guidelines between 3/2017 and 2/2018. Only questions with feedback-rates >50% were further analysed and ratios >90% defined “high agreement”, 70–90% “agreement”, 30–70% “insufficient agreement” and <30% “disagreement”. For diagnosis, we found insufficient agreement on using flow-cytometry, classifying MDS precursor conditions, performing treatment response assessment after hypomethylating agents (HMA) and evaluating patients with suspected germ-line predisposition. For risk-stratification, we identified agreement on using IPSS-R but insufficient agreement for IPSS and patient-based assessments. For treatment, we observed disagreement on performing primary infectious prophylaxis in neutropenia but agreement on using only darbepoetin alfa in anaemic, lower-risk MDS patients. For thrombopoietin receptor agonists, insufficient agreement was found for the indication, preferred agent and triggering platelet count. Insufficient agreement was also found for immunosuppressive treatment in hypoplastic MDS and HMA dose adjustments. In conclusion, we identified areas for improvement in MDS patient care, in need of further clinical trials, information, and guiding documents. Full article

Myelodysplastic syndromes (MDS) are heterogeneous clonal hematopoietic disorders characterized by ineffective hematopoiesis, bone marrow dysplasia, and peripheral cytopenias. Familial forms of MDS have traditionally been considered rare, especially in adults; however, the increasing availability of somatic and germline genetic analyses has identified multiple susceptibility loci. Bone marrow failure syndromes have been well-described in the pediatric setting, e.g., Fanconi anemia (FA), dyskeratosis congenita (DC), Diamond–Blackfan anemia (DBA), and Shwachman–Diamond syndrome (SBS), hallmarked by clinically-recognizable phenotypes (e.g., radial ray anomalies in FA) and significantly increased risks for MDS and/or acute myeloid leukemia (AML) in the setting of bone marrow failure. However, additional families with multiple cases of MDS or AML have long been reported in the medical literature with little known regarding potential hereditary etiologies. Over the last decade, genomic investigation of such families has revealed multiple genes conferring inherited risks for MDS and/or AML as the primary malignancy, including RUNX1, ANKRD26, DDX41, ETV6, GATA2, and SRP72. As these syndromes are increasingly appreciated in even apparently de novo presentations of MDS, it is important for hematologists/oncologists to become familiar with these newly-described syndromes. Herein, we provide a review of familial MDS syndromes and practical aspects of management in patients with predisposition syndromes. Full article