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  • 1
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    Genetic Determinants Of Disease Phenotype In Myelodysplastic Syndromes
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 2755-2755
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 2755-2755
    Abstract: Diagnosis of myelodysplastic syndromes (MDS) is greatly limited by the scarce reproducibility of morphological analysis of dysplasia and the poor specificity of dysplastic changes. In a group of myeloid disorders classified on the basis of morphological criteria, identifying specific associations between genotype and disease phenotypes is essential to recognize disease entities according to distinctive genetic profiles. These genotype-phenotype correlations are illustrated by the 5q- syndrome, and more recently by the association of SF3B1 mutations with ring sideroblasts, which makes SF3B1 the first gene to be strongly associated with a specific morphological feature in myeloid neoplasms. In this work, we performed a comprehensive mutation analysis in a large and well clinically characterized cohort of MDS patients, and sought for associations between genotype and disease phenotype. Massively parallel pyrosequencing was used to screen coding exons of 111 genes known to be implicated in myeloid neoplasms. We studied 245 patients diagnosed with MDS according to WHO criteria at the Department of Hematology, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Italy: 26 were classified as RA, 35 as RARS, 69 as RCMD, 27 as RCMD-RS, 10 MDS with isolated del(5q), 36 as RAEB-1, and 42 as RAEB-2. The most frequently mutated gene categories were splicing factors (122/245, 49.7%), chromatin modifiers (91/245, 37.1%), DNA methylation (71/245, 29%), transcription factors (58/245, 23. 7%), signalling (44/245, 18%), and RAS pathway (27/245, 11%). We first focused on nonsideroblastic MDS categories (RA, RCMD, RAEB-1, RAEB-2) with the aim to identify genetic determinants of multilineage dysplasia and excess of bone marrow blasts. We found that mutations of genes involved in DNA methylation (DNMT3A, TET2, IDH1, IDH2) were significantly associated with multilineage dysplasia or excess blasts (P=.007). In fact, of 48 patients carrying these mutant genes, only two had isolated erythroid dysplasia, whereas 26 of 48 showed multilineage dysplasia and 20 excess blasts. The positive predictive value of mutations in this gene category for multilineage dysplasia was 92.9%, and 95.8% for advanced disease, defined as either multilineage dysplasia or excess blasts. We then studied patients with mutations in splicing factors other than SF3B1 (SRSF2, U2AF1, ZRSR2), and found that, of 57 patients carrying these mutaions, 3 showed unilineage dysplasia, whereas multilineage dysplasia or excess blasts were observed in 27 patients each (P=.016), resulting in a positive predictive value for multilineage dysplasia of 90% and of 94.7% for advanced disease. Mutations in RAS pathway (KRAS, NRAS, CBL, NF1) were observed in 19 patients, 7 classified as RCMD and 12 as RAEB, whereas no cases with isolated erythroid dysplasia were observed (P=.033). The resulting positive predictive value of these mutations for multilineage dysplasia or excess blasts was of 100%. Finally, we found a significant association of RUNX1 mutations with advanced disease (P=.024), resulting in a positive predictive value for multilineage dysplasia of 83% and of 100% for advanced disease. Overall, having at least one mutation in genes involved in DNA methylation, splicing factors other than SF3B1, RAS pathway or in RUNX1 had a positive predictive value for multilineage dysplasia or excess blasts of 96.5%. We then focused on sideroblastic categories (RARS and RCMD-RS). A significantly different prevalence of SF3B1 mutations was observed in patients with isolated erythroid dysplasia versus multilineage dysplasia (91.4% in RARS vs 55.6% in RCMD-RS, P=.002). Conversely, a significantly higher prevalence of mutations in other splicing factors (SRSF2, U2AF1, ZRSR2) was found in patients with RCMD-RS compared with those with RARS (2.9% vs 22.2% respectively, P=.023). In conclusion, in a cohort of MDS patients well characterized with respect to clinical features and mutation status, we identified significant associations between genotype and disease phenotype. In particular, we found that mutations in genes involved in DNA methylation, splicing factors (other than SF3B1), RAS pathway and in RUNX1 are highly predictive of multilineage dysplasia and excess of BM blasts. These observations, together with the close association of SF3B1 with disease phenotype with ring sideroblasts, may represent the basis for a molecular classification of MDS. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.2755.2755
    RVK:
    XA 33000
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 2
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    Somatic Mutation of SF3B1, a Gene Encoding a Core Component of RNA Splicing Machinery, in Myelodysplasia with Ring Sideroblasts
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 3-3
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3-3
    Abstract: Abstract 3 Myelodysplastic syndromes (MDS) are myeloid neoplasms characterized by dysplasia in one or more cell lines, ineffective hematopoiesis, and variable risk of progression to acute myeloid leukemia (AML). As any other neoplasm, MDS is expected to be driven by mutation, and its clonal evolution is likely a multistep process in which several genetic events occur. Somatic mutations of TET2 have been found in about 25% of MDS patients, while additional mutant genes (including ASXL1, ETV6, EZH2, IDH1, IDH2, RUNX1, and TP53) have been detected in smaller proportions of patients, particularly in those with poor prognosis. Refractory anemia with ring sideroblasts (RARS) is a phenotypically well-defined subtype of MDS, characterized by 15% or more ring sideroblasts (RS, erythroblasts with perinuclear iron-loaded mitochondria) in the bone marrow. We reasoned that the identification of recurrently mutated genes in RARS could provide novel insights into molecular pathogenesis of MDS, and used massively parallel sequencing technology to identify somatically acquired point mutations across all protein-coding exons in the genome in 8 patients with RARS. We identified 62 point mutations across the 8 patients, and the mutation spectrum showed a predominance of transitions, especially C 〉 T/G 〉 A mutations. Within 5/8 patients studied, the observed proportion of reads reporting a mutant allele showed significantly greater variability than expected by chance, indicating that the population of malignant cells was genetically heterogeneous. In 6/8 RARS patients, we identified recurrent somatic mutations (found in granulocytes but not in T-lymphocytes) in a gene that encodes a core component of the RNA splicing machinery, SF3B1. Based on the proportion of reads reporting the mutant allele, the mutations all appeared to be heterozygous and present in the dominant clone of cells. To characterize the spectrum and frequency of SF3B1 mutations in greater detail, both in myeloid malignancies and other cancers, we undertook targeted resequencing of the gene. In particular, we studied patients with MDS, myelodysplastic/myeloproliferative neoplasm (MDS/MPN) or AML evolving from MDS. Somatic mutations of SF3B1 were found in 150/533 (28.1%) patients with MDS, 16/83 (19.3%) patients with MDS/MPN, and 2/38 (5.3%) patients with AML. The gene was also mutated in 1–5% of diverse other tumor types. All mutations appeared to be heterozygous substitutions, and we observed no frameshift indels, splice site mutations or nonsense substitutions. The mutations clustered in exons 12–15 of the gene, and K700E accounted for 97/168 (57.7%) of the variants observed. SF3B1 mutations were less deleterious than expected by chance, implying that the mutated protein retains structural integrity with altered function. Gene expression profiling revealed SF3B1 mutations are associated with down-regulation of key gene networks, including core mitochondrial pathways. Close relationships were found between mutant SF3B1 and presence of RS (P 〈 .001), and between mutant allele burden and percentage of RS (P=.002). Overall, 83/105 (79%) of patients with RARS, 30/54 (57.7%) of those with refractory cytopenia with multilineage dysplasia and RS, and 12/18 (66.7%) of those with RARS associated with marked thrombocytosis (RARS-T) carried a somatic mutation of SF3B1. On the other hand, 97% of patients carrying a mutant SF3B1 had RS, and the mutant gene had a positive predictive value for RS of 97.7% (95% CI, 93.5–99.5%). We then studied the prognostic significance of the genetic lesion. In multivariable analysis including established risk factors, SF3B1 mutations were independently associated with better overall survival (HR=0.18, P=.028) and lower risk of progression to AML (HR=0.32, P=.048). In conclusion, mutations in SF3B1 implicate abnormalities of mRNA splicing, a pathway not previously known as a target for mutation, in the pathogenesis of MDS. The close relationship between this molecular lesion and RS is consistent with a causal relationship, and makes SF3B1 the first gene to be strongly associated with a specific morphological feature in MDS. Finally, SF3B1 mutations are independent predictors of favorable clinical outcome, and their detection may improve risk assessment in MDS. The first two authors equally contributed to this paper, which is on behalf of the International Cancer Genome Consortium Chronic Myeloid Disorders Working Group. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.3.3
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
    detail.hit.zdb_id: 1468538-3
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  • 3
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    Clonal Analysis of SF3B1, JAK2 and MPL in Refractory Anemia with Ring Sideroblasts Associated with Marked Thrombocytosis
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 172-172
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 172-172
    Abstract: Abstract 172 Somatic mutations of the RNA splicing machinery have been recently identified in patients with myelodysplastic syndrome (MDS). In particular, a strong association has been found between SF3B1 mutation and the MDS subtype defined as refractory anemia with ring sideroblasts (RARS). Similarly, within myelodysplastic/myeloproliferative neoplasms (MDS/MPN) a high prevalence of SF3B1 mutations has been reported in the provisional entity defined as refractory anemia with ring sideroblasts associated with marked thrombocytosis (RARS-T). These findings strongly support a causal relationship between SF3B1 mutations and ring sideroblasts. Interestingly, a high proportion of RARS-T patients also harbor JAK2 and/or MPL mutations. The available evidence suggests that somatic mutations of SF3B1 might be an early pathogenetic event determining myelodysplastic features, and that subsequent occurrence of JAK2 and/or MPL mutations may cause the myeloproliferative phenotype. In this work, we studied the mutation status of SF3B1, JAK2 and MPL in circulating granulocytes and bone marrow cells from RARS-T patients. We also studied the in vitro growth of hematopoietic progenitors (BFU-E, CFU-GM), and genotyped individual colonies to examine the mutation status of the above genes. The coding exons of SF3B1 were screened using massively parallel pyrosequencing. A real time PCR-based allelic discrimination assay was used for the detection of JAK2 (V617F), while Sanger sequencing was employed for JAK2 exon 12 and MPL exon 10 mutation analysis. Twenty-eight patients affected with RARS-T were assessed for SF3B1, JAK2 and MPL exon 10 mutation status. Eighteen patients (64%) showed somatically acquired mutation of SF3B1. The median mutant allele burden was 43%, consistent with the presence in the majority of patients of clonal hematopoiesis characterized by a dominant clone carrying a heterozygous SF3B1 mutation. Fourteen patients carried the JAK2 (V617F) mutation (median allele burden 6.5%, range 0.4–29.5%), while one had a JAK2 exon 12 mutation. In 13 cases, the JAK2 mutation was detected at the time of diagnosis, whereas in 2 patients, who had a typical RARS phenotype and were negative for JAK2 mutations at clinical onset, JAK2 (V617F) was detected 18 and 32 months after diagnosis, respectively, and concomitantly with a progressive increase in platelet count. Four patients, two of whom were JAK2 (V617F)-positive, carried the MPL (W515L) mutation (median allele burden 27.5%, range 25–50%). Concomitant mutations of SF3B1 and JAK2 or MPL were observed in 8 cases. Seven patients carried an SF3B1 mutation and JAK2 (V617F), while one carried SF3B1 (K700E), JAK2 (V617F), and MPL (W515L). In all these cases, the SF3B1 mutant allele burden was higher than that of JAK2 or MPL, indicating the existence of an SF3B1-mutated dominant clone with minority JAK2- or MPL-mutated clones. We genotyped individual colonies from peripheral blood in 2 patients with concomitant mutations. In a patient with granulocyte SF3B1 and JAK2 mutant allele burdens equal to 45% and 8%, respectively, SF3B1 (H662Q) was detected in 9 of 11 colonies, three of which also carried JAK2 (V617F); the remaining two colonies had wild type SF3B1 and JAK2. These data are consistent with the existence of a dominant hematopoietic clone carrying the SF3B1 mutation and the subsequent emergence of a JAK2-mutated subclone. The other patient, who was initially SF3B1- mutated and JAK2 wild type, at the time of colony assay had a mutant allele burden equal to 50% and 1% for SF3B1 (K700E) and JAK2 (V617F), respectively. Forty-three of 45 colonies were heterozygous for SF3B1 (K700E) and wild type for JAK2. The opposite pattern was observed in the remaining 2 colonies, which carried just JAK2 (V617F). These data indicate the coexistence of two distinct clones, a dominant one carrying the SF3B1 mutation and a minority one carrying JAK2 (V617F). In summary, these observations suggest that the occurrence of an SF3B1 mutation represents an early event in patients with RARS-T, likely causing mitochondrial iron overload, ring sideroblasts, ineffective erythropoiesis and anemia, typical myelodysplastic features. The subsequent occurrence of a somatic mutation of JAK2 or MPL involves the emergence of minority clones and the acquisition of myeloproliferative features. JAK2- mutated clones may emerge as subclones of the dominant SF3B1-mutated clone or as independent clones. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.172.172
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
    detail.hit.zdb_id: 1468538-3
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  • 4
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    Integrating clinical features and genetic lesions in the risk assessment of patients with chronic myelomonocytic leukemia
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 10 ( 2016-09-08), p. 1408-1417
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 10 ( 2016-09-08), p. 1408-1417
    Abstract: Risk assessment is crucial in patients with CMML because survival may range from a few months to several years. Integrating clinical features, morphology, and genetic lesions significantly improves risk stratification in CMML.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2016-05-714030
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
    detail.hit.zdb_id: 1468538-3
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  • 5
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    The Effects of Mitochondrial Ferritin Expression in Normal and Sideroblastic Erythropoiesis.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 736-736
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 736-736
    Abstract: Abstract 736 In erythroid cells from patients with refractory anemia with ringed sideroblasts (RARS), the expression of mitochondrial ferritin (MtF) - encoded by the nuclear FTMT gene located on chromosome 5q21.3 - occurs at a very early stage of differentiation and is closely related to the sideroblastic phenotype [Blood. 2003 Mar 1;101(5):1996-2000]. On the other hand, in extra-hematopoietic tissues MtF expression is associated with high cellular metabolic activity and oxygen consumption, suggesting a possible role of this protein in protecting mitochondria from iron-dependent oxidative damage. It is known that reactive oxygen species (ROS) act as second messengers in the JAK/STAT pathway, which is involved in the regulation of erythropoiesis, and that ROS scavengers inhibit STAT5 phosphorylation. It was the aim of this study to investigate the influence of experimentally induced MtF over-expression on erythroid differentiation in normal hematopoietic progenitors, and in addition to define the relationship between MtF expression and erythroid maturation, apoptosis, and JAK-STAT pathway activation in RARS. A liquid culture model was adopted to expand erythroid progenitors from CD34+ cells in the presence of IL-3, IL-6, stem cell factor and Epo [Blood. 2005 Jul 1;106(1):247-53] . To study the effect of MtF induction in normal hematopoiesis, CD34+ cells from 5 healthy donors were transduced using lentivirus carrying cDNA of FTMT downstream to the ubiquitous PGK promoter (transduction efficiency equal to 30-40%), and then cultured for 21 days. To assess the effect of MtF expression in myelodysplastic syndromes (MDS), CD34+ cells from 24 patients with RARS, as well as cells from 20 patients with refractory anemia (RA) and from 8 healthy donors (as control groups) were cultured. Cytospins were performed for MtF, H-ferritin (HF) and L-ferritin (LF) immunocytochemical analysis, and samples of cultured cells were removed at various days of culture for biological studies. Lentivirus-mediated FTMT transduction of normal CD34+ progenitors did not inhibit cell growth nor prevent the differentiation of erythroid progenitors. By flow cytometry analysis, MtF-positive erythroid progenitors showed significantly reduced levels of HF and increased expression of transferrin receptor (CD71) compared with MtF-negative progenitors (P = .004 and P = .01, respectively). In this model, induction of MtF resulted in increased cellular apoptosis (median number of apoptotic cells by TUNEL assay at day 21 equal to 83% in MtF-positive cells vs 18% in MtF-negative cells, P 〈 .001). A significantly lower proliferation rate and higher apoptotic index were observed in cultures from patients with RARS and RA with respect to healthy controls. FTMT mRNA was detected by RT-PCR in CD34+ progenitor cells from patients with RARS, while protein expression was observed only from day 4 of culture, with a significant increase in the percentage of MtF-positive cells during culture (median value from 5% at day 4 to 24% at day 21, P = .002). No MtF expression was observed in RA patients. In MtF-positive cells from RARS patients, an inverse relationship between MtF and HF cellular content, and a direct relationship between MtF and CD71 expression were observed. In erythroid progenitors from RARS patients, the apoptotic rate was higher in MtF-positive than in MtF-negative cells (median number of apoptotic cells equal to 17% vs 6%, P 〈 .001). Finally, we analyzed by flow cytometry the relationship between MtF expression and STAT5 phosphorylation in cultured cells following Epo stimulation. Preliminary data from three RARS patients showed that p-STAT5 expression was lower in MtF-positive than in MtF-negative cells (P = .02). In conclusion, experimental overexpression of MtF in normal erythroid progenitors may reduce mitochondrial iron availability thus inducing apoptosis. In erythroid progenitors from RARS patients, the pathological expression of MtF is associated with increased apoptosis of immature red cells (ineffective erythropoiesis), which may be at least in part determined by reduced activation of the JAK-STAT pathway in response to Epo. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.736.736
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 6
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    MGUS and Chip: Two Faces, but Not of the Same Medal
    American Society of Hematology ; 2021
    In:  Blood Vol. 138, No. Supplement 1 ( 2021-11-05), p. 3800-3800
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    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 3800-3800
    Abstract: Clonal, pre-clinical expansions of hematopoietic cells are increasingly recognized. Clonal hematopoiesis of indeterminate potential (CHIP) has been recently described. It is characterized by the presence of mutations usually involved in myeloid neoplasia in people without any sign of hematological malignancy. Well before CHIP, another pre-clinical clonal expansion has been described for plasma cells (PC) based on the presence of a serum monoclonal protein, namely monoclonal gammopathy of undetermined significance (MGUS). Despite both being frequent, the association between these two bone marrow (BM) clonal entities has not been determined yet. Since the incidence of MGUS and CHIP rises with age reaching & gt;10% of people & gt;70y, we analyzed a unique oldest-old population dataset to define a possible association between these two different BM clonal disorders. We analyzed a cohort of 777 patients with a median age of 91 years (range, 81 - 104), significantly higher than previous studies on MGUS. 579 (74.5%) were females and 198 (25.5%) males. CHIP was assessed in all but 45 through sequencing of a myeloid specific gene panel. Serum protein electrophoresis was available in all of them to assess the prevalence of MGUS. The prevalence of CHIP and MGUS were 17.5% (128/732) and 9.5% (74/777), respectively. Importantly, CHIP and MGUS did not associate in our cohort but rather showed a non-significant trend towards anti-correlation (Fisher's Exact test, p-val = 0.09). We then tested associations with different clinical and laboratory features, finding that, as expected, MGUS associated with higher concentration of gamma-globulins (Wilcoxon test, p-val = 0.01414), but also with absolute lower levels of albumin (Wilcoxon test, p-val = 0.01398). No significant association was found with the mean corpuscular value (MCV), hemoglobin levels or age. These results were confirmed by a logistic univariate model, in which also the male gender resulted associated with the presence of a monoclonal component with borderline significance. Then, to further corroborate our results we performed univariate linear regression analyses. Given that CHIP and MGUS are mainly considered two aging conditions, we investigated in linear regression models the impact of age, as a continuous variable, on other clinical features. In particular, we observed that the increase of age was significantly correlated with lower albumin levels (F-stat: 1.921e+04, Adj R-squared: 0.9288, p-val: & lt; 2.2e-16), decreasing hemoglobin concentration (F-stat: 1.434e+05, Adj R-squared: 0.9898, p-val & lt; 2.2e-16), increasing levels of gamma-globulins (F-stat: 9.21e+04, Adj R-squared: 0.9843, p-val & lt; 2.2e-16) and higher MCV (F-stat: 18.04, Adj R-squared: 0.01144, p-val 2.3e-05). Then, a significant anti-correlation between gamma-globulin and serum albumin levels was also confirmed (F-stat: 2.807e+04, Adj R-squared: 0.9501, p-val & lt; 2.2e-16). Finally, we implemented two different multivariate logistic models using as independent variables the presence or absence of MGUS or CHIP, respectively. In these models, the presence of a monoclonal component was only positively associated with a higher level of gamma-globulins (Est: 0.16238, p-val = 0.00079) and not with increasing age (Est: 0.02680, p-val = 0.31819). Interestingly, the presence of an MGUS confirmed a tendency to an anti-correlation with the presence of CHIP (Est: -0.78959, p-val = 0.06468). On the contrary, CHIP as independent variable resulted significantly correlated with increasing age (Est: 0.07396, p-val = 0.00021). The spectrum of mutations in CHIP cases with or without MGUS was not significantly different, with DNMT3A and TET2 being the most frequently mutated genes. Our study shows that, in a large cohort of oldest-old patients, CHIP and MGUS are not correlated but follow two seemingly independent patterns, showing a tendency to a mutual exclusivity and associating with different clinical and laboratory values. One limitation of our study is the skewing towards female sex, where MGUS is less prevalent, but this is explained by the cohort's median age knowing that females have a longer expected life. Based on this, our findings that CHIP but not MGUS increased with age in our cohort suggest different selective pressures in this extreme age range. These results warrant further investigation as to whether there could be age-specific drivers for MGUS, and their clinical relevance. Disclosures Bolli: Amgen: Honoraria; Takeda: Honoraria; Janssen: Consultancy, Honoraria; Celgene/BMS: Consultancy, Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2021-147890
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
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  • 7
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    Clinical relevance of clonal hematopoiesis in persons aged ≥80 years
    American Society of Hematology ; 2021
    In:  Blood Vol. 138, No. 21 ( 2021-11-25), p. 2093-2105
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    In: Blood, American Society of Hematology, Vol. 138, No. 21 ( 2021-11-25), p. 2093-2105
    Abstract: Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of cancers and inflammation-related diseases. This phenomenon becomes common in persons aged ≥80 years, in whom the implications of CHIP are not well defined. We performed a mutational screening in 1794 persons aged ≥80 years and investigated the relationships between CHIP and associated pathologies. Mutations were observed in one-third of persons aged ≥80 years and were associated with reduced survival. Mutations in JAK2 and splicing genes, multiple mutations (DNMT3A, TET2, and ASXL1 with additional genetic lesions), and variant allele frequency ≥0.096 had positive predictive value for myeloid neoplasms. Combining mutation profiles with abnormalities in red blood cell indices improved the ability of myeloid neoplasm prediction. On this basis, we defined a predictive model that identifies 3 risk groups with different probabilities of developing myeloid neoplasms. Mutations in DNMT3A, TET2, ASXL1, or JAK2 were associated with coronary heart disease and rheumatoid arthritis. Cytopenia was common in persons aged ≥80 years, with the underlying cause remaining unexplained in 30% of cases. Among individuals with unexplained cytopenia, the presence of highly specific mutation patterns was associated with myelodysplastic-like phenotype and a probability of survival comparable to that of myeloid neoplasms. Accordingly, 7.5% of subjects aged ≥80 years with cytopenia had presumptive evidence of myeloid neoplasm. In summary, specific mutational patterns define different risk of developing myeloid neoplasms vs inflammatory-associated diseases in persons aged ≥80 years. In individuals with unexplained cytopenia, mutational status may identify those subjects with presumptive evidence of myeloid neoplasms.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.2021011320
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
    detail.hit.zdb_id: 1468538-3
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  • 8
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    A Prognostic Model for Predicting the Impact of Comorbidities on Survival of Patients with Myelodysplastic Syndromes.
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 2453-2453
    Details
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 2453-2453
    Abstract: Myelodysplastic syndromes (MDS) occur mainly in older persons, and these patients are likely to have comorbidities. We studied the impact of comorbidities on non-leukemic death (NLD) and overall survival (OS) in MDS patients with the aim of developing a specific prognostic index. Eight hundred forty consecutive patients receiving a diagnosis of MDS at Policlinico San Matteo, Pavia, Italy, between 1992 and 2006 were retrospectively evaluated. One or more comorbidities were present in 455/840 (54%) patients: the older the age, the higher their prevalence (P & lt;0.001). Cardiac disease was observed in 25% of patients, liver disease in 16%, diabetes in 11%, prior solid tumor in 10%, nephropathy and pulmonary disease in 4%. Non-leukemic causes of death included cardiac failure (63%), infection (24%) and hemorrhage (7%). In a Cox analysis with age, sex, WHO category, cytogenetics and transfusion-dependency as time-dependent covariates, the presence of one or more comorbidities significantly affected both the risk of NLD (HR=1.91, P=0.001) and OS (HR=1.51, P=0.01), while it did not influence the risk of leukemic progression. The negative effect of comorbidities on OS was more evident in patients without excess of blasts (HR=1.8 P=0.007), while it retained a borderline significance in patients with more advanced disease (P=0.05). By including comorbidities as distinct entities in multivariable analysis, cardiac failure, liver or pulmonary disease, and solid tumors were found to independently affect the risk of NLD (HR=3.7, HR=2.08, HR=2.07 HR=2.23, respectively; P values from & lt;0.001 to 0.033). Based on results of uni- and multivariable analysis, we developed a prognostic model for predicting the effect of comorbidities on NLD and OS. For each comorbidity, risk scores were estimated from the coefficients of the Cox regression. This MDS-specific comorbidity index (MDS-CI) allowed us to identify 3 groups of patients with different probability of NLD and OS (HR 2.78, P & lt;0.001; HR 1.67 P=0.001), and provided a better stratification than the available non MDS-specific indices. Focusing on WPSS categories [J Clin Oncol2007; 25:3503–10], MDS-CI significantly stratified survival of patients with very-low, low and intermediate risk groups (P & lt;0.001), while it had no effect in high and very-high risk groups. We then investigated the relationship between transfusion-dependency, secondary iron overload and comorbidities. Heart failure (28% vs. 18% P=0.001) and cardiac death (69% vs 55% P=0.03) were significantly more frequent in transfusion-dependent patients. In a Cox analysis with time-dependent covariates, transfusion-dependent patients showed an increased risk of NLD (HR=2.12 P= & lt;0.001), heart failure (HR 1.34 P=0.03), and cardiac death (HR 2.99 P=0.01). The development of secondary iron overload significantly affected the risk of NLD and OS (HR=1.25 and 1.16 respectively, P & lt;0.001), and this effect was maintained after adjusting for transfusion burden. Iron overload specifically increased the risk of developing heart failure (HR=1.17, P & lt;0.001). In summary, the presence of non-hematological comorbidities significantly worsens the survival of MDS patients. Transfusion-dependency and secondary iron overload are associated with an increased risk of cardiac complications and cardiac death. The MDS-CI might be a useful tool for clinical decision making in patients with myelodysplastic syndromes.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V110.11.2453.2453
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 9
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    Erythroid Activity, Transfusion Iron Overload, and Hepcidin Levels in Patients with Myelodysplastic Syndrome
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 2676-2676
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 2676-2676
    Abstract: The vast majority of patients with myelodysplastic syndrome (MDS) present with anemia, and many of them become transfusion dependent in the long term. Although transfusion iron is primarily taken up by the reticuloendothelial cells, the metal is later redistributed to parenchymal cells, and a portion of MDS patients develop parenchymal iron overload, which may have a negative impact on survival (N Engl J Med2005;352:536–8). The redistribution of transfusion iron from macrophages to parenchymal cells is likely to be modulated by hepcidin levels and erythroid activity. In fact, hepcidin prevents the release of iron from macrophages, and its synthesis is partly down-regulated by erythroid activity, which varies considerably within MDS patients. Expanded but ineffective erythropoiesis is the major mechanism responsible for anemia in low-risk MDS patients, particularly in those with refractory anemia with ringed sideroblasts, while erythroid marrow hypoproliferation is generally found in high-risk patients, typically in those with excess of blasts. We studied 76 patients with MDS followed at the Department of Hematology Oncology, University of Pavia & Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. The WHO classification criteria were employed for diagnosis of MDS. Median time since diagnosis was 12 months (range 0–241). Twenty-five patients were RBC transfusion-dependent (median number of RBC units received was 15, range 4–160). Erythroid activity was evaluated through measurement of soluble transferrin receptor (sTfR) and serum Epo, while body iron status was assessed through serum iron, TIBC and serum ferritin (sFtn). Serum hepcidin was quantified by laser desorption ionization time-of-flight mass spectrometry preceded by weak cation-exchange chromatography exploiting des-Asp hepcidin (hepcidin-24) as an internal standard (www.hepcidinanalysis.com or PLoS ONE2008;16;3:e2706). sTfR levels were found to be independently associated with hemoglobin (Hb) (the higher Hb, the lower sTfR; P & lt;.001), serum Epo (the higher Epo, the lower sTfR; P & lt;.001), and WHO category (patients with purely erythroid disorders having higher values than those with multilineage dysplasia and excess blasts; P & lt;.001), as well as with sFtn (the higher sFtn, the lower sTfR; P=.02). A wide variability in hepcidin level was found in MDS patients (median 6.98 nM, range 0.18–92.05 nM). Patients with pure erythroid disorders had significantly lower hepcidin levels compared with those with multilineage dysplasia or excess of blasts (median values 4.41, 7.62, and 15.31 nM, respectively; P & lt;.001). Transfusion-dependent patients had significantly higher hepcidin levels compared with transfusion-independent subjects (15.31 vs 4.73 nM, P & lt;.001). Significant linear correlations were found between serum hepcidin and Hb (r=−.28, P=0.02), serum Epo (r=.44, P & lt;.001), sFtn (r=.68, P & lt;.001) and sTfR (r=−.64, P & lt;.001). Considering all MDS patients, multivariable analysis showed that serum hepcidin levels were independently determined by sTfR levels (the higher sTfR, the lower serum hepcidin; P & lt;.001) and sFtn (the higher sFtn, the higher serum hepcidin; P & lt;.001). Restricting multivariable analysis to MDS patients receiving regular blood transfusion, the presence of ring sideroblasts and their number were also found to have an independent, negative impact of serum hepcidin levels (P=.005). These findings suggest that in MDS patients the redistribution of transfusion iron from reticuloendothelial cells to parenchymal cells is influenced by erythroid activity through its effect on serum hepcidin levels. MDS patients with expanded but ineffective erythropoiesis have low levels of hepcidin and enhanced iron release from macrophages, and therefore a higher likelihood of parenchymal iron loading. In particular, patients with refractory anemia with ring sideroblasts show low hepcidin levels in spite of iron overload, and therefore appear to be at high risk of parenchymal organ damage. Since these this condition has a benign clinical course, preventing organ damage through iron chelation therapy appears clinically important.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.2676.2676
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 10
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    Differential Expression of Genes Related to JAK-STAT Pathway Activation or Megakaryocyte Differentiation/Maturation in CD34+ Cells from Patients with Refractory Anemia with Ringed Sideroblasts and Thrombocytosis (RARS-T).
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 397-397
    Details
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 397-397
    Abstract: A peculiar feature of the myelodysplastic syndrome (MDS) defined as refractory anemia with ringed sideroblasts (RARS) is that CD34+ cells have a distinct expression profile characterized by up-regulation of mitochondrial-related genes and, in particular, of those of heme synthesis, e.g., ALAS2 [Blood2006;108:337–45]. RARS-T is a poorly defined myelodysplastic/myeloproliferative variant of RARS. RARS-T patients may carry the JAK2 (V617F) mutation, and this might considerably affect gene expression. We did studies of JAK2 and MPL mutation analysis, and of gene expression profiling in 16 RARS-T patients. We employed a real time PCR-based allelic discrimination assay for the detection of JAK2 (V617F), and direct sequencing for the analysis of JAK2 exon 12 and MPL exon 10 mutations. The Affymetrix microarray technology (U133 Plus2.0 chips) was used for gene expression profiling of purified bone marrow CD34+ cells. Mutations of JAK2 and/or MPL were detected in granulocytes but not T-lymphocytes from 7/16 patients (44%). Five patients carried JAK2 (V617F), one patient had the JAK2 exon 12 E543-D544del, and the remaining patient had both JAK2 (V617F) and MPL (W515L) mutant alleles. Granulocytes carrying mutant alleles represented only a minor fraction of clonal granulocytes, as determined by X-chromosome inactivation patterns. By comparing gene expression profiles of CD34+ cells from 12 RARS and 6 RARS-T patients (4 of these latter carrying mutant JAK2 alleles), 255 genes were found to be differentially expressed. Within the 165 up-regulated genes, the most represented ones included genes related to transcription regulation, cell proliferation, and cytoskeleton organization. Within the 90 down-regulated genes, those related to cell cycle arrest and cell adhesion were the most recurrent ones. Forty-six genes were found to be differentially expressed in all 6 RARS-T cases, and 8 of these showed a relative expression ratio & gt;2. In particular, CXCR4, a gene encoding a CXC chemokine receptor specific for SDF-1 and reported to be down-regulated in primary myelofibrosis, was markedly down-regulated in RARS-T patients. JCTSG (encoding cathepsin) and JLTF (encoding lactoferrin and inhibited by STAT5 activation) were also markedly down-regulated. A significant up-regulation of TNRC15, a gene involved in the signal transduction by insulin-like growth factor (IGF-I), was observed. Finally, a few genes involved in cytoskeleton organization and megakaryocyte differentiation/maturation (like CDC2L5, ARHGAP12, and PLDN) were found to be differentially expressed. Thus, in refractory anemia with ringed sideroblasts, clonal hematopoietic cells may acquire not only JAK2 (V617F), but also of JAK2 exon 12 and MPL exon 10 mutations. The occurrence of JAK2 and MPL mutations, and possibly of additional ones, results in CD34+ cell expression profiles consistent with activation of the JAK-STAT pathway and enhancement of megakaryocytopoiesis.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V110.11.397.397
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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