Luca Malcovati

Austrian Academy of Sciences, Wien, Vienna, Austria

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Publications (146)879.98 Total impact

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    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.
    Leukemia. 11/2014;
  • Luca Malcovati, Elisa Rumi, Mario Cazzola
    Haematologica 11/2014; 99(11):1650-2. · 5.94 Impact Factor
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    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.
    Blood 10/2014; · 9.78 Impact Factor
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    ABSTRACT: The selection of a treatment strategy before allogeneic hematopoietic stem cell transplant (HSCT) for myelodysplastic syndrome is a delicate process. The expected relapse risk and nonrelapse mortality after HSCT and the response rates to the pretransplant strategies all play a role in this process. Fit patients younger than 60 to 65 years with > 10% marrow blasts and without high-risk cytogenetic abnormalities should be seriously considered for intensive chemotherapy (ICT) to reduce tumor load before HSCT. Other patients up to the age of 75 years may be considered for hypomethylating agent therapy before transplant. Patients with high-risk cytogenetic abnormalities should be treated in investigational protocols if they are not candidates for ICT. Copyright © 2014 Elsevier Inc. All rights reserved.
    Clinical lymphoma, myeloma & leukemia. 09/2014; 14S:S42-S45.
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    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.
    Blood 06/2014; · 9.78 Impact Factor
  • Cancer Cell 06/2014; · 24.76 Impact Factor
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    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.
    Leukemia. 05/2014;
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    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.
    Blood 02/2014; · 9.78 Impact Factor
  • Haematologica 01/2014; 99(1):e8-e10. · 5.94 Impact Factor
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    ABSTRACT: Background Approximately 50 to 60% of patients with essential thrombocythemia or primary myelofibrosis carry a mutation in the Janus kinase 2 gene (JAK2), and an additional 5 to 10% have activating mutations in the thrombopoietin receptor gene (MPL). So far, no specific molecular marker has been identified in the remaining 30 to 45% of patients. Methods We performed whole-exome sequencing to identify somatically acquired mutations in six patients who had primary myelofibrosis without mutations in JAK2 or MPL. Resequencing of CALR, encoding calreticulin, was then performed in cohorts of patients with myeloid neoplasms. Results Somatic insertions or deletions in exon 9 of CALR were detected in all patients who underwent whole-exome sequencing. Resequencing in 1107 samples from patients with myeloproliferative neoplasms showed that CALR mutations were absent in polycythemia vera. In essential thrombocythemia and primary myelofibrosis, CALR mutations and JAK2 and MPL mutations were mutually exclusive. Among patients with essential thrombocythemia or primary myelofibrosis with nonmutated JAK2 or MPL, CALR mutations were detected in 67% of those with essential thrombocythemia and 88% of those with primary myelofibrosis. A total of 36 types of insertions or deletions were identified that all cause a frameshift to the same alternative reading frame and generate a novel C-terminal peptide in the mutant calreticulin. Overexpression of the most frequent CALR deletion caused cytokine-independent growth in vitro owing to the activation of signal transducer and activator of transcription 5 (STAT5) by means of an unknown mechanism. Patients with mutated CALR had a lower risk of thrombosis and longer overall survival than patients with mutated JAK2. Conclusions Most patients with essential thrombocythemia or primary myelofibrosis that was not associated with a JAK2 or MPL alteration carried a somatic mutation in CALR. The clinical course in these patients was more indolent than that in patients with the JAK2 V617F mutation. (Funded by the MPN Research Foundation and Associazione Italiana per la Ricerca sul Cancro.).
    New England Journal of Medicine 12/2013; · 54.42 Impact Factor
  • Luca Malcovati, Mario Cazzola
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    ABSTRACT: Refractory anemia with ring sideroblasts (RARS) is a subtype of myelodysplastic syndrome (MDS) characterized by 15% or more ring sideroblasts in the bone marrow according to the WHO classification. After Perls staining, ring sideroblasts are defined as erythroblasts in which there are 5 or more siderotic granules covering at least a third of the nuclear circumference. The iron deposited in perinuclear mitochondria of ring sideroblasts is present in the form of mitochondrial ferritin. The molecular basis of MDS with ring sideroblasts has remained unknown until recently. In 2011, whole exome sequencing studies revealed somatic mutations of SF3B1, a gene encoding a core component of RNA splicing machinery, in myelodysplasia with ring sideroblasts. The close relationship between SF3B1 mutation and ring sideroblasts is consistent with a causal relationship, and makes SF3B1 the first gene to be associated with a specific morphological feature in MDS. RARS is mainly characterized by isolated anemia due to ineffective erythropoiesis, and its clinical course is generally benign, although there is a tendency to worsening of anemia in most patients over time. By contrast, refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS) is characterized by pancytopenia and dysplasia in two or more myeloid cell lineages. More importantly, patients with RCMD-RS have a higher risk of developing bone marrow failure or progressing to acute myeloid leukemia (AML). Refractory anemia with ring sideroblasts (RARS-T) associated with marked thrombocytosis is a myelodysplastic/myeloproliferative neoplasm associated with both SF3B1 and JAK2 or MPL mutations. RARS-T may develop from an SF3B1 mutated RARS through the acquisition of a JAK2 or MPL mutations in a subclone of hematopoietic cells.
    Best practice & research. Clinical haematology 12/2013; 26(4):377-385. · 3.13 Impact Factor
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    ABSTRACT: Myelodysplasia is a diagnostic feature of myelodysplastic syndromes (MDS) but is found also in other myeloid neoplasms. Its molecular basis has been recently elucidated by means of massive parallel sequencing studies. About 90% of MDS patients carry one or more oncogenic mutations, and two thirds of them are found in individuals with normal karyotype. Driver mutant genes include those of RNA splicing (SF3B1, SRSF2, U2AF1, ZRSR2), DNA methylation (TET2, DNMT3A, IDH1/2), chromatin modification (ASXL1, EZH2), transcription regulation (RUNX1), DNA repair (TP53), signal transduction (CBL, NRAS, KRAS), and cohesin complex (STAG2). Only 4-6 genes are consistently mutated in 10% or more MDS patients, while a long tail of about 50 genes are mutated less frequently. At presentation, most patients typically have 2 or 3 driver oncogenic mutations and hundreds of background mutations. MDS driver genes are frequently mutated also in other myeloid neoplasms. Reliable genotype/phenotype relationships include the association of SF3B1 mutation with refractory anemia with ring sideroblasts, TET2/SRSF2 co-mutation with chronic myelomonocytic leukemia, and activating CSF3R mutation with chronic neutrophilic leukemia. Although both founding and subclonal driver mutations have been shown to have prognostic significance, prospective clinical trials that include the molecular characterization of the patient's genome are now needed.
    Blood 10/2013; · 9.78 Impact Factor
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    ABSTRACT: Myelodysplastic syndromes (MDS) are a heterogeneous group of chronic hematological malignancies characterized by dysplasia, ineffective hematopoiesis and a variable risk of progression to acute myeloid leukemia. Sequencing of MDS genomes has identified mutations in genes implicated in RNA splicing, DNA modification, chromatin regulation and cell signaling. We sequenced 111 genes across 738 patients with MDS or closely related neoplasms (including CMML and MDS-MPN) to explore the role of acquired mutations in MDS biology and clinical phenotype. 78% patients had one or more oncogenic mutations. We identify complex patterns of pairwise association between genes, indicative of epistatic interactions involving components of the spliceosome machinery and epigenetic modifiers. Coupled with inferences on subclonal mutations, these data suggest a hypothesis of genetic 'predestination', in which early driver mutations, typically affecting genes involved in RNA splicing, dictate future trajectories of disease evolution with distinct clinical phenotypes. Driver mutations had equivalent prognostic significance whether clonal or subclonal, and leukemia-free survival deteriorated steadily as numbers of driver mutations increased. Thus, analysis of oncogenic mutations in large, well-characterized cohorts of patients illustrates the interconnections between the cancer genome and disease biology, with considerable potential for clinical application.
    Blood 09/2013; · 9.78 Impact Factor
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    ABSTRACT: The diagnosis of patients with myelodysplastic syndromes (MDS) is largely dependent on morphologic examination of bone marrow aspirates. Several criteria that form the basis of the classifications and scoring systems most commonly used in clinical practice are affected by operator-dependent variation. To identify standardized molecular markers that would allow prediction of prognosis, we have used gene expression profiling (GEP) data on CD34+ cells from patients with MDS to determine the relationship between gene expression levels and prognosis. GEP data on CD34+ cells from 125 patients with MDS with a minimum 12-month follow-up since date of bone marrow sample collection were included in this study. Supervised principal components and lasso penalized Cox proportional hazards regression (Coxnet) were used for the analysis. We identified several genes, the expression of which was significantly associated with survival of patients with MDS, including LEF1, CDH1, WT1, and MN1. The Coxnet predictor, based on expression data on 20 genes, outperformed other predictors, including one that additionally used clinical information. Our Coxnet gene signature based on CD34+ cells significantly identified a separation of patients with good or bad prognosis in an independent GEP data set based on unsorted bone marrow mononuclear cells, demonstrating that our signature is robust and may be applicable to bone marrow cells without the need to isolate CD34+ cells. We present a new, valuable GEP-based signature for assessing prognosis in MDS. GEP-based signatures correlating with clinical outcome may significantly contribute to a refined risk classification of MDS.
    Journal of Clinical Oncology 09/2013; · 18.04 Impact Factor
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    ABSTRACT: With the aim of reviewing critical concepts and producing recommendations for the management of chronic myelomonocytic leukemia, key questions were selected according to the criterion of clinical relevance. Recommendations were produced using a Delphi process and four consensus conferences involving a panel of experts appointed by the Italian Society of Hematology and affiliated societies. This report presents the final statements and recommendations, covering patient evaluation at diagnosis, diagnostic criteria, risk classification, first-line therapy, monitoring, second-line therapy and allogeneic stem cell transplantation. For the first-line therapy, the panel recommended that patients with myelodysplastic-type chronic myelomonocytic leukemia and less than 10% blasts in bone marrow should be managed with supportive therapy aimed at correcting cytopenias. In patients with myelodysplastic-type chronic myelomonocytic leukemia with a high number of blasts in bone marrow (≥10%), supportive therapy should be integrated with the use of 5-azacytidine. Patients with myeloproliferative-type chronic myelomonocytic leukemia with a low number of blasts (<10%) should be treated with cytoreductive therapy. Hydroxyurea is the drug of choice to control cell proliferation and to reduce organomegaly. Patients with myeloproliferative-type chronic myelomonocytic leukemia, and a high number of blasts should receive polychemotherapy. Both in myelodysplastic-type and myeloproliferative-type chronic myelomonocytic leukemia, allogeneic stem cell transplantation should be offered within clinical trials in selected patients.
    Haematologica 09/2013; 98(9):1344-52. · 5.94 Impact Factor
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    ABSTRACT: Within the MDS work-package of the European LeukemiaNet, an Expert Panel was selected according to the framework elements of the NIH Consensus Development Program. A systematic review of the literature was performed including indexed original papers, indexed reviews and educational papers, and abstracts of conference proceedings. Guidelines were developed based on a list of patient- and therapy-oriented questions, and recommendations were formulated and ranked according to the supporting level of evidence. MDS should be classified according to the 2008 WHO criteria. An accurate risk-assessment requires not only the evaluation of disease-related factors, but also of those related to extra-hematological comorbidity. The assessment of individual risk enables the identification of fit patients with a poor prognosis, who are candidates for up-front intensive treatments, primarily allogeneic stem cell transplantation. A high proportion of MDS patients are not eligible for potentially curative treatment because of advanced age and/or clinically relevant comorbidities and poor performance status. In these patients, the therapeutic intervention is aimed at preventing cytopenia-related morbidity and preserving quality of life. A number of new agents are being developed, for which the available evidence is not sufficient to recommend routine use. The inclusion of patients into prospective clinical trials is strongly recommended.
    Blood 08/2013; · 9.78 Impact Factor
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    ABSTRACT: Allogeneic hematopoietic stem cell transplantation (HSCT) represents the only curative treatment for patients with myelodysplastic syndrome (MDS), but involves non-negligible morbidity and mortality. Registry studies have shown that advanced disease stage at transplantation is associated with inferior overall survival. To define the optimal timing of allogeneic HSCT, we carried out a decision analysis by studying 660 patients who received best supportive care and 449 subjects who underwent transplantation. Risk assessment was based on both the International Prognostic Scoring System (IPSS) and the World Health Organization classification-based Prognostic Scoring System (WPSS). We used a continuous-time multistate Markov model to describe the natural history of disease and evaluate the effect of allogeneic HSCT on survival. This model estimated life expectancy from diagnosis according to treatment policy at different risk stages. Relative to supportive care, estimated life expectancy increased when transplantation was delayed from the initial stages until progression to intermediate-1 IPSS-risk or to intermediate WPSS-risk stage, and then decreased for higher risks. Modeling decision analysis on WPSS versus IPSS allowed better estimation of the optimal timing of transplantation. These observations indicate that allogeneic HSCT offers optimal survival benefits when the procedure is performed before MDS patients progress to advanced disease stages. Am. J. Hematol. 88:581–588, 2013. © 2013 Wiley Periodicals, Inc.
    American Journal of Hematology 07/2013; 88(7). · 4.00 Impact Factor
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    ABSTRACT: PURPOSEMyelodysplastic syndromes (MDS) are clonal hematopoietic disorders that are more common in patients aged ≥ 60 years and are incurable with conventional therapies. Reduced-intensity conditioning (RIC) allogeneic hematopoietic stem-cell transplantation is potentially curative but has additional mortality risk. We evaluated RIC transplantation versus nontransplantation therapies in older patients with MDS stratified by International Prognostic Scoring System (IPSS) risk. PATIENTS AND METHODSA Markov decision model with quality-of-life utility estimates for different MDS and transplantation states was assessed. Outcomes were life expectancy (LE) and quality-adjusted life expectancy (QALE). A total of 514 patients with de novo MDS aged 60 to 70 years were evaluated. Chronic myelomonocytic leukemia, isolated 5q- syndrome, unclassifiable, and therapy-related MDS were excluded. Transplantation using T-cell depletion or HLA-mismatched or umbilical cord donors was also excluded. RIC transplantation (n = 132) stratified by IPSS risk was compared with best supportive care for patients with nonanemic low/intermediate-1 IPSS (n = 123), hematopoietic growth factors for patients with anemic low/intermediate-1 IPSS (n = 94), and hypomethylating agents for patients with intermediate-2/high IPSS (n = 165).ResultsFor patients with low/intermediate-1 IPSS MDS, RIC transplantation LE was 38 months versus 77 months with nontransplantation approaches. QALE and sensitivity analysis did not favor RIC transplantation across plausible utility estimates. For intermediate-2/high IPSS MDS, RIC transplantation LE was 36 months versus 28 months for nontransplantation therapies. QALE and sensitivity analysis favored RIC transplantation across plausible utility estimates. CONCLUSION For patients with de novo MDS aged 60 to 70 years, favored treatments vary with IPSS risk. For low/intermediate-1 IPSS, nontransplantation approaches are preferred. For intermediate-2/high IPSS, RIC transplantation offers overall and quality-adjusted survival benefit.
    Journal of Clinical Oncology 06/2013; · 18.04 Impact Factor
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    ABSTRACT: In myelodysplastic syndromes with ring sideroblasts (MDS-RS), the iron deposited in the mitochondria of RS is present in the form of mitochondrial ferritin (FTMT), but it is unknown whether FTMT overexpression is the cause or the result of mitochondrial iron deposition. Lentivirus FTMT-transduced CD34(+) bone marrow cells from seven healthy donors and CD34(+) cells from 24 patients with MDS-RS were cultured according to a procedure that allowed the expansion of high numbers of erythroid progenitors. These cells were used to investigate the possible influence of experimentally-induced FTMT overexpression on normal erythropoiesis and the functional effects of FTMT in sideroblastic erythropoiesis. In MDS-RS progenitors, FTMT overexpression was associated with reduced cytosolic ferritin levels, increased surface transferrin receptor expression and reduced cell proliferation; FTMT effects were independent of SF3B1 mutation status. Similarly, FTMT overexpressing normal erythroid progenitors were characterized by reduced cytosolic ferritin content and increased CD71 expression, and also by higher apoptotic rate in comparison with the FTMT- controls. Significantly lower levels of STAT5 phosphorylation following erythropoietin stimulation were found in both sideroblastic and normal FTMT(+) erythroid cells compared to the FTMT- cells. In conclusion, experimental overexpression of FTMT may modify mitochondrial iron availability and lead to ineffective erythropoiesis.
    British Journal of Haematology 04/2013; · 4.94 Impact Factor
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    ABSTRACT: The natural course of chronic myelomonocytic leukemia (CMML) is highly variable but a widely accepted prognostic scoring system for patients with CMML is not available. The main aim of this study was to develop a new CMML-specific prognostic scoring system (CPSS) in a large series of 558 patients with CMML (training cohort, Spanish Group of Myelodysplastic Syndromes) and to validate it in an independent series of 274 patients (validation cohort, Heinrich-Heine-University Hospital, Düsseldorf, Germany and San Matteo Hospital, Pavia, Italy). The most relevant variables for overall survival (OS) and evolution to acute myeloblastic leukemia (AML) were FAB and WHO CMML subtypes, CMML-specific cytogenetic risk classification, and RBC transfusion dependency. CPSS was able to segregate patients into four clearly different risk groups for OS (P< .001) and risk of AML evolution (P< .001) and its predictive capability was confirmed in the validation cohort. An alternative CPSS with hemoglobin instead of RBC transfusion dependency offered almost identical prognostic capability. This study confirms the prognostic impact of FAB and WHO subtypes, recognizes the importance of RBC transfusion dependency and cytogenetics and offers a simple and powerful CPSS for accurately assessing prognosis and planning therapy in patients with CMML.
    Blood 01/2013; · 9.78 Impact Factor

Publication Stats

4k Citations
879.98 Total Impact Points

Institutions

  • 2011–2013
    • Austrian Academy of Sciences
      • Research Center for Molecular Medicine
      Wien, Vienna, Austria
    • Ospedale di San Raffaele Istituto di Ricovero e Cura a Carattere Scientifico
      Milano, Lombardy, Italy
  • 1998–2013
    • University of Pavia
      • Department of Public Health, Neuroscience, Experimental and Forensic Medicine
      Ticinum, Lombardy, Italy
    • Policlinico San Matteo Pavia Fondazione IRCCS
      • s.c. Radiologia - Istituto di Radiologia
      Ticinum, Lombardy, Italy
  • 2008–2010
    • Karolinska Institutet
      • Department of Medicine, Huddinge
      Stockholm, Stockholm, Sweden
    • University of Oxford
      • Nuffield Division of Clinical Laboratory Sciences
      Oxford, ENG, United Kingdom
  • 2006–2009
    • Oxford University Hospitals NHS Trust
      • Nuffield Department of Clinical Laboratory Sciences
      Oxford, England, United Kingdom