[Show abstract][Hide abstract] ABSTRACT: Patients with transfusion-dependent myelodysplastic syndromes (MDS) have an increased risk of cardiac events, due to both chronic anemia and iron overload. Here, we report the recovery of cardiac function after an intensive iron chelation therapy in a MDS patient who had developed heart failure due to iron overload.
[Show abstract][Hide abstract] ABSTRACT: Purpose of review:
This article will review the most recent advances in the understanding of the genetic basis of myeloid neoplasms with myelodysplasia and will discuss its clinical implications.
Recurrent somatic mutations have been identified in about 90% of patients with myeloid neoplasms with myelodysplasia, involving genes of RNA splicing, DNA methylation, histone modification, transcription regulation, DNA repair, signal transduction, and cohesin complex. Somatic mutations are acquired in a linear manner in a multipotent hematopoietic stem cell, resulting in a growth advantage at the stem cell level and in defective differentiation and maturation of hematopoietic precursors. Recently, evidence has been provided of age-related hematopoietic clones, driven by mutations of genes recurrently mutated in myeloid neoplasms. These hematopoietic clones may represent either premalignant clones with the potential to progress to myeloid neoplasm or small malignant clones at a preclinical stage.
The available evidence clearly indicates that greater understanding of the molecular basis of myeloid neoplasms with myelodysplasia has relevant implications in the classification of these disorders, as well as in predicting disease risk and response to specific treatment modalities, and may open avenues of research leading to novel therapeutic options and personalized treatment in the individual patient.
Current opinion in oncology 09/2015; 27(6). DOI:10.1097/CCO.0000000000000229 · 4.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A risk-adapted treatment strategy is mandatory for myelodysplastic syndromes (MDS). We refined the WHO-classification based Prognostic Scoring System (WPSS) by determining the impact of the newer clinical and cytogenetic features and we compared its prognostic power to that of the revised International Prognostic Scoring System (IPSS-R). A population of 5326 untreated MDS was considered. We analyzed single WPSS parameters and confirmed that WHO classification and severe anemia provide important prognostic information in MDS. A strong correlation was found between the WPSS including the new cytogenetic risk stratification and WPSS adopting original criteria. We then compared WPSS vs. IPSS-R prognostic system. A highly significant correlation was found between the WPSS and IPSS-R risk classifications. Discrepancies did occur among lower-risk patients in whom the number of dysplastic hematopoietic lineages as assessed by morphology did not reflect the severity of peripheral blood cytopenias and/or increased marrow blast count. Moreover, severe anemia has higher prognostic weight in the WPSS vs. IPSS-R model. Overall both systems well represent the prognostic risk of MDS patients defined by WHO morphologic criteria. This study provides relevant information for the implementation of risk-adapted strategies in MDS.Leukemia accepted article preview online, 27 February 2015. doi:10.1038/leu.2015.55.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 02/2015; 29(7). DOI:10.1038/leu.2015.55 · 10.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cancer is a genetic disease, but two patients rarely have identical genotypes. Similarly, patients differ in their clinicopathological parameters, but how genotypic and phenotypic heterogeneity are interconnected is not well understood. Here we build statistical models to disentangle the effect of 12 recurrently mutated genes and 4 cytogenetic alterations on gene expression, diagnostic clinical variables and outcome in 124 patients with myelodysplastic syndromes. Overall, one or more genetic lesions correlate with expression levels of ~20% of all genes, explaining 20-65% of observed expression variability. Differential expression patterns vary between mutations and reflect the underlying biology, such as aberrant polycomb repression for ASXL1 and EZH2 mutations or perturbed gene dosage for copy-number changes. In predicting survival, genomic, transcriptomic and diagnostic clinical variables all have utility, with the largest contribution from the transcriptome. Similar observations are made on the TCGA acute myeloid leukaemia cohort, confirming the general trends reported here.
[Show abstract][Hide abstract] ABSTRACT: The splicing factor SF3B1 is the most commonly mutated gene in the myelodysplastic syndromes (MDS), particularly in patients with refractory anemia with ring sideroblasts (RARS). We investigated the functional effects of SF3B1 disruption in myeloid cell lines: SF3B1 knockdown resulted in growth inhibition, cell cycle arrest and impaired erythroid differentiation, and deregulation of many genes and pathways, including cell cycle regulation and RNA processing. MDS is a disorder of the hematopoietic stem cell and we thus studied the transcriptome of CD34(+) cells from MDS patients with SF3B1 mutations using RNA-sequencing. Genes significantly differentially expressed at the transcript and/or exon level in SF3B1 mutant compared to wildtype cases include genes involved in MDS pathogenesis (ASXL1, CBL), iron homeostasis and mitochondrial metabolism (ALAS2, ABCB7, SLC25A37) and RNA splicing/processing (PRPF8, HNRNPD). Many genes regulated by a DNA damage-induced BRCA1-BCLAF1-SF3B1 protein complex showed differential expression/splicing in SF3B1 mutant cases. This is the first study to determine the target genes of SF3B1 mutation in MDS CD34+ cells. Our data indicate that SF3B1 plays a critical role in MDS by affecting the expression and splicing of genes involved in specific cellular processes/pathways, many of which are relevant to the known RARS pathophysiology, suggesting a causal link.Leukemia accepted article preview online, 27 November 2014. doi:10.1038/leu.2014.331.
[Show abstract][Hide abstract] ABSTRACT: Despite the recent identification of recurrent SETBP1 mutations in Atypical Chronic Myeloid Leukemia (aCML), a complete description of the somatic lesions responsible for the onset of this disorder is still lacking. To find additional somatic abnormalities in aCML, we performed whole-exome sequencing on 15 aCML cases. In 2 cases (13.3%) we identified somatic missense mutations in the ETNK1 gene. Targeted resequencing on 515 hematological clonal disorders revealed the presence of ETNK1 variants in 6/68 aCML (9%) and 2/77 chronic myelomonocytic leukemia samples (3%). These mutations clustered in a small region of the kinase domain, encoding for H243Y and N244S (1/8 H243Y; 7/8 N244S), they were all heterozygous and present in the dominant clone. Intracellular phosphoethanolamine/phosphocholine ratio was, on average, 5.2-fold lower in ETNK1-mutated samples (p-value < 0.05). Similar results were obtained using myeloid TF1 cells transduced with ETNK1 Wild-Type, ETNK1-N244S and ETNK1-H243Y, where the intracellular phosphoethanolamine/phosphocholine ratio was significantly lower in ETNK1-N244S (0.76±0.07) and ETNK1-H243Y (0.37±0.02) than in ETNK1-WT (1.37±0.32; p=0.01 and p=0.0008, respectively), suggesting that ETNK1 mutations may inhibit the catalytic activity of the enzyme. In summary, our study shows for the first time the evidence of recurrent somatic ETNK1 mutations in the context of MDS/MPN disorders.
[Show abstract][Hide abstract] ABSTRACT: Our knowledge of the genetic basis of myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) has considerably improved. To define genotype/phenotype relationships of clinical relevance, we studied 308 patients with MDS, MDS/MPN or acute myeloid leukemia evolving from MDS. Unsupervised statistical analysis, including the World Health Organization (WHO) classification criteria and somatic mutations, showed that MDS associated with SF3B1-mutation (51/245 patients, 20.8%) is a distinct nosologic entity irrespective of current morphological classification criteria. Conversely, MDS with ring sideroblasts with nonmutated SF3B1 segregated in different clusters with other MDS subtypes. Mutations of genes involved DNA methylation, splicing factors other than SF3B1, and genes of the RAS pathway and cohesin complex were independently associated with multilineage dysplasia and identify a distinct subset (51/245 patients, 20.8%). No recurrent mutation pattern correlated with unilineage dysplasia without ring sideroblasts. Irrespective of driver somatic mutations, a threshold of 5% bone marrow blasts retained a significant discriminant value for identifying cases with clonal evolution. Co-mutation of TET2 and SRSF2 was highly predictive of a myeloid neoplasm characterized by myelodysplasia and monocytosis, including but not limited to chronic myelomonocytic leukemia. These results serve as a proof of concept that a molecular classification of myeloid neoplasms is feasible.
[Show abstract][Hide abstract] ABSTRACT: Evidence for distinct human cancer stem cells (CSCs) remains contentious and the degree to which different cancer cells contribute to propagating malignancies in patients remains unexplored. In low- to intermediate-risk myelodysplastic syndromes (MDS), we establish the existence of rare multipotent MDS stem cells (MDS-SCs), and their hierarchical relationship to lineage-restricted MDS progenitors. All identified somatically acquired genetic lesions were backtracked to distinct MDS-SCs, establishing their distinct MDS-propagating function in vivo. In isolated del(5q)-MDS, acquisition of del(5q) preceded diverse recurrent driver mutations. Sequential analysis in del(5q)-MDS revealed genetic evolution in MDS-SCs and MDS-progenitors prior to leukemic transformation. These findings provide definitive evidence for rare human MDS-SCs in vivo, with extensive implications for the targeting of the cells required and sufficient for MDS-propagation.
Cancer Cell 06/2014; DOI:10.1016/j.ccr.2014.03.036 · 23.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The World Health Organization classification of myelodysplastic syndromes (MDS) is based on morphological evaluation of marrow dysplasia. We performed a systematic review of cytological and histological data from 1150 patients with peripheral blood cytopenia. We analyzed the frequency and discriminant power of single morphological abnormalities. A score to define minimal morphological criteria associated to the presence of marrow dysplasia was developed. This score showed high sensitivity/specificity (>90%), acceptable reproducibility and was independently validated. The severity of granulocytic and megakaryocytic dysplasia significantly affected survival. A close association was found between ring sideroblasts and SF3B1 mutations, and between severe granulocytic dysplasia and mutation of ASXL1, RUNX1, TP53 and SRSF2 genes. In myeloid neoplasms with fibrosis, multilineage dysplasia, hypolobulated/multinucleated megakaryocytes and increased CD34+ progenitors in the absence of JAK2, MPL and CALR gene mutations were significantly associated with a myelodysplastic phenotype. In myeloid disorders with marrow hypoplasia, granulocytic and/or megakaryocytic dysplasia, increased CD34+ progenitors and chromosomal abnormalities are consistent with a diagnosis of MDS. The proposed morphological score may be useful to evaluate the presence of dysplasia in cases without a clearly objective myelodysplastic phenotype. The integration of cytological and histological parameters improves the identification of MDS cases among myeloid disorders with fibrosis and hypocellularity.Leukemia advance online publication, 17 June 2014; doi:10.1038/leu.2014.161.
[Show abstract][Hide abstract] ABSTRACT: About one third of patients with myelodysplastic syndrome (MDS) receiving allogeneic hematopoietic stem cell transplantation (HSCT) are cured by this treatment. Treatment failure may be due to transplant complications or relapse. In order to identify predictive factors for transplantation outcome, we studied 519 patients with MDS or oligoblastic acute myeloid leukemia (AML, <30% marrow blasts) who received allogeneic an HSCT and were reported to the GITMO registry between 2000 and 2011. Univariate and multivariate survival analyses were performed using Cox proportional hazards regression. High-risk category, as defined by the IPSS-R, and monosomal karyotype were independently associated with relapse and lower overall survival after transplantation. On the other hand, older recipient age and high hematopoietic cell transplantation-comorbidity index (HCT-CI) were independent predictors of non-relapse mortality. Accounting for various combinations of patient's age, IPSS-R category, monosomal karyotype, and HCT-CI, the 5-year probability of survival after allogeneic HSCT ranged from 0 to 94%. This study indicates that IPSS-R risk category and monosomal karyotype are important factors predicting transplantation failure both in MDS and oligoblastic AML. In addition, it reinforces the concept that allogeneic HSCT offers optimal eradication of myelodysplastic hematopoiesis when the procedure is performed before MDS patients progress to advanced disease stages.