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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
    detail.hit.zdb_id: 1468538-3
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  • 2
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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
    Details
    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
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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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
    detail.hit.zdb_id: 80069-7
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  • 4
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    Functional Impact of Genomic Complexity on the Transcriptome of Multiple Myeloma
    American Association for Cancer Research (AACR) ; 2021
    In:  Clinical Cancer Research Vol. 27, No. 23 ( 2021-12-01), p. 6479-6490
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 27, No. 23 ( 2021-12-01), p. 6479-6490
    Abstract: Multiple myeloma is a biologically heterogenous plasma-cell disorder. In this study, we aimed at dissecting the functional impact on transcriptome of gene mutations, copy-number abnormalities (CNA), and chromosomal rearrangements (CR). Moreover, we applied a geno-transcriptomic approach to identify specific biomarkers for personalized treatments. Experimental Design: We analyzed 514 newly diagnosed patients from the IA12 release of the CoMMpass study, accounting for mutations in multiple myeloma driver genes, structural variants, copy-number segments, and raw-transcript counts. We performed an in silico drug sensitivity screen (DSS), interrogating the Cancer Dependency Map (DepMap) dataset after anchoring cell lines to primary tumor samples using the Celligner algorithm. Results: Immunoglobulin translocations, hyperdiploidy and chr(1q)gain/amps were associated with the highest number of deregulated genes. Other CNAs and specific gene mutations had a lower but very distinct impact affecting specific pathways. Many recurrent genes showed a hotspot (HS)-specific effect. The clinical relevance of double-hit multiple myeloma found strong biological bases in our analysis. Biallelic deletions of tumor suppressors and chr(1q)-amplifications showed the greatest impact on gene expression, deregulating pathways related to cell cycle, proliferation, and expression of immunotherapy targets. Moreover, our in silico DSS showed that not only t(11;14) but also chr(1q)gain/amps and CYLD inactivation predicted differential expression of transcripts of the BCL2 axis and response to venetoclax. Conclusions: The multiple myeloma genomic architecture and transcriptome have a strict connection, led by CNAs and CRs. Gene mutations impacted especially with HS-mutations of oncogenes and biallelic tumor suppressor gene inactivation. Finally, a comprehensive geno-transcriptomic analysis allows the identification of specific deregulated pathways and candidate biomarkers for personalized treatments in multiple myeloma.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-20-4366
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 5
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    Driver somatic mutations identify distinct disease entities within myeloid neoplasms with myelodysplasia
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 9 ( 2014-08-28), p. 1513-1521
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    In: Blood, American Society of Hematology, Vol. 124, No. 9 ( 2014-08-28), p. 1513-1521
    Abstract: Different driver mutations have distinct effects on phenotype of myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). Accounting for driver mutations may allow a classification of these disorders that is considerably relevant for clinical decision-making.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2014-03-560227
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
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  • 6
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    Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 24 ( 2011-12-08), p. 6239-6246
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    In: Blood, American Society of Hematology, Vol. 118, No. 24 ( 2011-12-08), p. 6239-6246
    Abstract: In a previous study, we identified somatic mutations of SF3B1, a gene encoding a core component of RNA splicing machinery, in patients with myelodysplastic syndrome (MDS). Here, we define the clinical significance of these mutations in MDS and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). The coding exons of SF3B1 were screened using massively parallel pyrosequencing in patients with MDS, MDS/MPN, or acute myeloid leukemia (AML) evolving from MDS. Somatic mutations of SF3B1 were found in 150 of 533 (28.1%) patients with MDS, 16 of 83 (19.3%) with MDS/MPN, and 2 of 38 (5.3%) with AML. There was a significant association of SF3B1 mutations with the presence of ring sideroblasts (P 〈 .001) and of mutant allele burden with their proportion (P = .002). The mutant gene had a positive predictive value for ring sideroblasts of 97.7% (95% confidence interval, 93.5%-99.5%). In multivariate analysis including established risk factors, SF3B1 mutations were found to be independently associated with better overall survival (hazard ratio = 0.15, P = .025) and lower risk of evolution into AML (hazard ratio = 0.33, P = .049). The close association between SF3B1 mutations and disease phenotype with ring sideroblasts across MDS and MDS/MPN is consistent with a causal relationship. Furthermore, SF3B1 mutations are independent predictors of favorable clinical outcome, and their incorporation into stratification systems might improve risk assessment in MDS.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2011-09-377275
    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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  • 7
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    Clinical and Molecular Features Of Myeloid Neoplasms Carrying SRSF2 Mutation
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 1532-1532
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 1532-1532
    Abstract: Mutations in genes encoding RNA splicing factors have been recently identified in myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). SRSF2 mutations have been reported in up to 20% of patients with MDS and in about 40 to 50% of those with chronic myelomonocytic leukemia (CMML). In this latter condition, SRFS2 is the second recurrently mutated gene after TET2, and a significant association between TET2 and SRSF2 mutations has been reported. In MDS, SRSF2 mutations have been associated with a poor prognosis and shortened overall survival and leukemia-free survival, but no clear correlation has been described so far with specific disease phenotype. Aims In this work, we studied a large and well characterized cohort of MDS and MDS/MPN patients with the aim to describe clinical and molecular features of myeloid neoplasms carrying SRSF2 mutations, to recognize patterns of co-occurring or mutually exclusive mutations, and to identify correlations with disease phenotypes. Methods Massively parallel pyrosequencing was used to screen coding exons of 111 genes implicated in myeloid malignancies in 267 patients with MDS or MDS/MPN according to WHO criteria, diagnosed at the Department of Hematology, Fondazione IRCCS Policlinico S. Matteo, University of Pavia, Italy. Two-hundred forty five patients were classified as MDS (26 RA; 35 RARS; 69 RCMD; 27 RCMD-RS; 10 MDS with isolated del(5q); 36 RAEB-1 and 42 RAEB-2), and 22 as MDS/MPN (20 CMML and 2 MDS/MPN, unclassifiable, MDS/MPN-U). Results High-confidence oncogenic mutations were identified in 43 genes, with a median number of 2 mutations per patient (range 0-9). In the MDS/MPN cohort, the most frequent mutations involved SRSF2 (10/22, 45%), TET2 (10/22, 45%) and ASXL1 (5/22, 23%). Seven of 10 (70%) patients with SRSF2 mutation also had a mutation in TET2. SRSF2-mutated patients showed significantly higher hemoglobin level (12.1 vs 9.3 g/dL, P 〈 .001 ) and higher monocyte count (2.42 vs 2.18 x109/L, P=.007) compared to those wild-type for SRSF2. Only 1 of 10 (10%) patients with SRSF2 mutations showed ring sideroblasts in the bone marrow. Among MDS patients, mutations of SRSF2 were observed in 34/245 (14%); significant associations were found with ASXL1 ( 9/34, 26%, P=.027) and IDH 1/2 (9/34, 26%, P 〈 .001). Conversely, mutations of DNMT3A and SF3B1 were mutually exclusive with SRSF2 mutations (0/34, P 〈 .001), while no significant association with TET2 mutations was demonstrated (6/34, 18%, P=ns). A significant association was found between SRSF2 mutations and multilineage dysplasia or excess blasts (2/34 patients with unilineage dysplasia, 16/34 with multilineage dysplasia and 16/34 with RAEB, P=.028). Moreover, SRSF2 mutations were significantly associated with the presence of a variable proportion of bone marrow ring sideroblasts (range 1-68%) (17 of 34 patients, 50%, P=.04). The cases with ring sideroblasts were classified according to WHO criteria as RA or RARS (2), RCMD or RCMD-RS (9), RAEB-1 or RAEB-2 (6). No significantly different mutation pattern was observed in SRSF2-mutated patients with or without ring sideroblasts. Finally, we investigated with an unsupervised approach in our whole cohort of myeloid neoplasms whether mutations of SRSF2 isolated or in association with co-occurring mutations could generate specific disease phenotypes. We found that the association of SRSF2 and TET2 mutations was highly specific for CMML disease phenotype (specificity 97.5%). Interestingly, of the six double mutated patients with a diagnosis of MDS, two showed relative monocytosis at the time of the analysis and two developed an overt CMML during follow-up. When accounting for these cases, the co-occurrence of SRSF2 and TET2 mutations showed specificity and positive predictive value for myelomonocytic phenotype of 99.2% and 84.6% respectively. Conclusions SRSF2 mutations are significantly associated with multilineage dysplasia and bone marrow ring sideroblasts in MDS patients, whereas the co-occurrence of SRSF2 and TET2 mutations is highly specific for the myelomonocytic phenotype of CMML. These data suggest that SRSF2 mutation is associated per se with a specific phenotype (ring sideroblasts and multilineage dysplasia), but also that its phenotypic impact may be modulated through interaction with other mutant genes like TET2. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.1532.1532
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 8
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    Revealing Transcriptome Deregulation upon Genomic Complexity in Multiple Myeloma
    American Society of Hematology ; 2020
    In:  Blood Vol. 136, No. Supplement 1 ( 2020-11-5), p. 3-4
    Details
    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 3-4
    Abstract: Introduction Multiple Myeloma (MM) is characterized by hyperdiploidy (HD) or immunoglobulin gene (IgH) rearrangements as initiating events. Clonal heterogeneity is a hallmark of its biology as highlighted by Next Generation Sequencing. In this context, data on the impact of peculiar mutations, copy number aberrations (CNAs), and chromosomal rearrangements (CRs) at the transcriptomic level are still scanty. In this study, we aimed to dissect the transcriptional deregulation promoted by the most recurrent genomic drivers. Based on this geno-trascriptomic link, we also aimed to identify biomarkers that could suggest personalized treatments. Methods We analyzed 517 newly diagnosed patients from the IA12 release of the CoMMpass study, focusing on mutations in MM driver genes, structural variants, copy number segments and raw transcript counts. RNAseq data was processed with the VOOM/LIMMA pipeline. To perform an in-silico drug sensitivity screen, we anchored cell lines to patients samples using the Celligner algorithm and interrogated the DepMap dataset. Results We first analyzed the global impact of genetic aberrations on the transcriptome. Chr(1q)amp/gain, followed by IgH translocations and HD showed the highest number of deregulated transcripts. Individual mutations had much less impact, with the exception of NRAS and chr(13q) genes (DIS3, TGDS, RB1). Next, we investigated differential influence between hotspots (HS) vs nonHS mutations within driver genes. KRAS and NRAS, showed little changes between nonHS and wild type (WT), as the transcriptome was mostly impacted by HS mutations. IRF4 K123 showed a specific transcriptional profile, while nonHS mutations still carried functional relevance although on different genes. For BRAF, the kinase dead D594 mutation surprisingly impacted the most in comparison to V600 and WT cases. Next, we explored the effect of bi-allelic genetic events with known prognostic impact. TP53 double-hits were associated with an upregulation of PHF19, a MM poor prognostic marker, and downregulation of SLAMF7, a new immunotherapy target. CYLD and TRAF3 double-hits correlated with NF-κB pathway activation, and the former showed a significant BCL2 upregulation. Bi-allelic events on chr13 exhibited gene-specific consequences: DIS3 inactivation deregulated mostly lncRNAs, while TGDS impacted on genes involved in cell-cycle regulation. Regarding chromosomal gains, only chr(1q)amp ( & gt; 3 copies) showed a gene dosage effect with upregulation of the potential therapeutic targets MCL1 and SLAMF7. Given that the BCL2 axis was perturbated by several genetic alterations, we systematically compared the expression levels of BCL2, NOXA, MCL1 and BCL2L1 in CYLD inactivated, t(11;14) and chr(1q)amp patients. BCL2 levels were higher in the CYLD group, which parallels with the overexpression of the anti-apoptotic gene BCL2L1. NOXA, which promotes MCL1 degradation, was significantly upregulated in t(11;14). Chr(1q)amp patients showed a concomitant MCL1 overexpression and NOXA downregulation. To correlate these results to drug sensitivity, we performed an in-silico screen. We first selected MM and lymphoma cell lines from the DepMap dataset based on a gene expression profile that was most similar to the MM samples, then analyzed candidate drugs. The SKMM2 MM cell line, harboring t(11;14), del(CYLD) e NOXAamp was highly sensitive to Venetoclax. The same was true for the lymphoma ones RI1 and OCI-LY3, both harboring NOXAamp, but negative for t(11;14). On the contrary, the U266 and MOLP8 both with t(11;14) carrying a MCL1amp due to a chr(1q)amp were fully resistant. Of note, these latter resulted sensitive to the pan-BCL2 axis inhibitor Sabutoclax. Conclusions Our study suggests a link between the genomic architecture and transcriptome in MM, where CNAs and CRs had a stronger impact on expression than gene mutations. However, given that not all mutations are identical, HS ones need further testing as they may represent a future treatment target. Moreover, the mutational status is crucial since, while mono-allelic events are often of little transcriptional value, compound heterozygosity carries a huge influence on transcriptomic which provides biological basis for the observed prognostic impact of "double-hit" MM. Finally, we suggest that a comprehensive profiling of the BCL2 pathway may identify biomarkers of sensitivity to BCL2 inhibitors in addition to the t(11;14). Disclosures D'Agostino: GSK: Membership on an entity's Board of Directors or advisory committees. Corradini:Celgene: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Incyte: Consultancy; Daiichi Sankyo: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other; BMS: Other; F. Hoffman-La Roche Ltd: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Novartis: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Servier: Consultancy, Honoraria; Kite: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations paid by for; KiowaKirin: Consultancy, Honoraria. Bolli:Celgene: Honoraria; Janssen: Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2020-136211
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 9
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    MGUS and clonal hematopoiesis show unrelated clinical and biological trajectories in an older population cohort
    American Society of Hematology ; 2022
    In:  Blood Advances Vol. 6, No. 21 ( 2022-11-08), p. 5702-5706
    Details
    In: Blood Advances, American Society of Hematology, Vol. 6, No. 21 ( 2022-11-08), p. 5702-5706
    Abstract: Monoclonal gammopathy of undetermined significance (MGUS) and clonal hematopoiesis (CH) are 2 preclinical clonal expansions of hematopoietic cells whose prevalence rises with age, reaching almost 10% in people of aged 70 years and older. The increased risk of myeloid malignancies in patients with myeloma is well defined, and the study of the association between CH and MGUS could help explain this phenomenon. Here, we analyzed a fully clinically annotated dataset of 777 older subjects (median age, 91 years) previously screened for prevalence of CH. The prevalence of MGUS and CH was 9.6% and 17.3%, respectively. We detected CH in 9.7% of the patients with MGUS and MGUS in 5.5% of the patients with CH. We did not find a significant correlation between the presence of MGUS and CH. Furthermore, the 2 conditions showed a differential association with clinical and laboratory covariates, suggesting that MGUS and CH may represent age-associated unrelated clonal drifts of hematopoietic cells. Confirmatory studies are needed to assess the relevance of CH in plasma cell disorders. This trial was registered at www.clinicaltrials.gov as #NCT03907553.
    Type of Medium: Online Resource
    ISSN: 2473-9529 , 2473-9537
    URL: Article
    DOI: 10.1182/bloodadvances.2021006498
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2022
    detail.hit.zdb_id: 2876449-3
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  • 10
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    Network meta‐analysis of randomized trials in multiple myeloma: Efficacy and safety in frontline therapy for patients not eligible for transplant
    Wiley ; 2022
    In:  Hematological Oncology Vol. 40, No. 5 ( 2022-12), p. 987-998
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    In: Hematological Oncology, Wiley, Vol. 40, No. 5 ( 2022-12), p. 987-998
    Abstract: The treatment scenario for newly‐diagnosed transplant‐ineligible multiple myeloma patients (NEMM) is quickly evolving. Currently, combinations of proteasome inhibitors and/or immunomodulatory drugs +/− the monoclonal antibody Daratumumab are used for first‐line treatment, even if head‐to‐head comparisons are lacking. To compare efficacy and safety of these regimens, we performed a network meta‐analysis of 27 phase 2/3 randomized trials including a total of 12,935 patients and 23 different schedules. Four efficacy/outcome and one safety indicators were extracted and integrated to obtain (for each treatment) the surface under the cumulative ranking‐curve (SUCRA), a metric used to build a ranking chart. With a mean SUCRA of 83.8 and 80.08 respectively, VMP + Daratumumab (DrVMP) and Rd + Daratumumab (DrRd) reached the top of the chart. However, SUCRA is designed to work for single outcomes. To overcome this limitation, we undertook a dimensionality reduction approach through a principal component analysis, that unbiasedly grouped the 23 regimens into three different subgroups. On the bases of our results, we demonstrated that first line treatment for NEMM should be based on DrRd (most active, but continuous treatment), DrVMP (quite “fixed‐time” treatment), or, alternatively, VRD and that, surprisingly, melphalan as well as Rd doublets still deserve a role in this setting.
    Type of Medium: Online Resource
    ISSN: 0278-0232 , 1099-1069
    URL: Issue
    URL: Article
    DOI: 10.1002/hon.v40.5
    DOI: 10.1002/hon.3041
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2001443-0
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