DICHIARAZIONE Relatore: DANIELA PIETRA
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1 DICHIARAZIONE Relatore: DANIELA PIETRA Come da nuova regolamentazione della Commissione Nazionale per la Formazione Continua del Ministero della Salute, è richiesta la trasparenza delle fonti di finanziamento e dei rapporti con soggetti portatori di interessi commerciali in campo sanitario. Posizione di dipendente in aziende con interessi commerciali in campo sanitario (NIENTE DA DICHIARARE) Consulenza ad aziende con interessi commerciali in campo sanitario (NIENTE DA DICHIARARE) Fondi per la ricerca da aziende con interessi commerciali in campo sanitario (NIENTE DA DICHIARARE) Partecipazione ad Advisory Board (NIENTE DA DICHIARARE) Titolarietà di brevetti in compartecipazione ad aziende con interessi commerciali in campo sanitario (NIENTE DA DICHIARARE) Partecipazioni azionarie in aziende con interessi commerciali in campo sanitario (NIENTE DA DICHIARARE) Altro
2 Somatic mutations of CALR in myeloproliferative neoplasms Daniela Pietra Division of Hematology Department of Oncology and Hematology Fondazione IRCCS Policlinico San Matteo Pavia University of Pavia Medical School
3 The genetic basis of MPN PV ET PMF % 95% 41% 59% 47% 53% ex12 MPL ex12 5% 95% 37% MPL 4% 59% 40% MPL 7% 53%
4 CALR ex9 somatic mutations in MPN WES on genomic DNA from granulocytes and CD 3+ T-cells from 6 PMF identified recurrently somatic mutations in CALR The screening of a cohort of 896 MPN patients identified 150 cases (17%) with indels in CALR 0/382 PV 78/311 ET (25%) 72/203 PMF (35%) All CALR-pos patients were negative for and MPL Klampfl et al. NEJM 2013;369:
5 The genetic basis of MPN PV ET PMF % 95% 41% 59% 47% 53% ex12 MPL ex12 5% 95% 37% MPL 4% 59% 40% MPL 7% 53% 2013 CALR ex12 5% 95% CALR 25% 12% MPL 4% 59% CALR 35% 5% MPL 7% 53%
6 A novel C-term peptide in mutant CALR N- domain P- domain C- domain KDEL Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 5 5 UTR 3 UTR Ex. 6 Ex. 7 Ex. 8 Ex. 9 Both impaired Ca-binding activity and cellular dislocation may play a role in the abnormal proliferation of cells expressing a mutant CALR Klampfl et al. NEJM 2013;369: Unpublished data
7 Genetic and functional analysis of CALR e128 RAMPAL et al mutations BLOOD, 29 MAY 2014 x VOLUME 123, NUMBER 22 e128 RAMPAL et al BLOOD, 29 MAY 2014 x VOLUME 123, NUMBER 22 Klampfl et al. NEJM 2013;369: Rampal et al. Blood 2014;123:e123-e133 Figure 3. CALR-mutant MPN patients are characterized by a gene signature associated with activated signaling. (A) Mutational status of, CALR, and MPL mutational status as well as clinical MPN diagnosis in 290 MPN patients. An individual column represents each patient. (B) GSEA showing enrichment of shrna signature in MPN patients with CALR mutations relative to normal subjects. (C) Heatmap representation of the 433 significantly differentially expressed genes (413 genes upregulated and 20 downregulated; FDR,0.01 and FC.2) in granulocytes from CALR-mutant MPN patients relative to normal subjects (21 MPN patients and 11 normal subjects). A red-blue color scale depicts normalized gene expression levels (red: high; blue: low). (D) GSEA showing significant enrichment of CALR-mutant MPN signature in MPN patients with homozygous mutations relative to normal subjects. Figure 3. CALR-mutant MPN patients are characterized by a gene signature associated with activated signaling. (A) Mutational status of, CALR, and MPL mutational status as well as clinical MPN diagnosis in 290 MPN patients. An individual column represents each patient. (B) GSEA showing enrichment of shrna
8 (solid cancers, used as controls), -mutated polycythemia vera, ET and PMF patients; MPL-mutated ET or PMF (n ¼ 8); /MPL/CALR triple-negative patients; CALR-mutated ET or PMF patients, including the CALRdel52, CALRins5 and CALRindel (ins5 0 -TCCTTCAG-delGCAGAGAAACAAATGAAGGACAAACAGGACG-3 0 ) CALR primarly affect (n ¼ 2) mutations. Results are presented in Figure 2. Subjects with non-hematologic disorders (not shown), MPN patients harboring the and MPLW515 mutation and triple-negative ET and PMF patients, all resulted negative with the biology of megakaryocytes the antibody raised against anti-mutated calreticulin (panel 2a). Conversely, the three variants of CALR mutations showed strong immunostaining (panel 2b), thus establishing the specificity of the fainter in myeloid and erythroid cells, compared with m yocytes (Figures 3e and f). Preferential expression of calreticulin in cells of megakar lineage We then asked whether the much more pronounced observed in megakaryocytes compared with cells of the and erythroid cell lineages was a consequence of the ac of the CALR mutation itself or rather it reflected a ph megakaryocytic lineage-associated overexpression of ca To this end, we used a commercially available antibody against the N terminus of calreticulin, therefore expected Klampfl et al. NEJM 2013;369: Vannucchi et al. Leukemia 2014;28: Figure 3. Immunostaining of bone marrow biopsies with the anti-mutated CALR antibody. Panel a shows two megakaryocytes labele anti-mutated calreticulin antibody together with a negative one. In panel b, abnormal, small megakaryocytes in the bone mar CALRins5 PMF patient are shown. Panel c shows a low-resolution picture of an advanced fibrosis in a CALRdel52 patient and d is a hig field from panel c (square) to show the abnormally shaped large megakaryocytes within buddles of fibers. In panels e and f, the fain
9 From bloodjournal.hematologylibrary.org at POLICLINICO S. MATTEO AMMINISTRAZIONE on March 17, For personal use only RUMI et al BLOOD, 6 MARCH 2014 x VOLUME 123, NUMBER 10 The impact of CALR mutations on ET Table 2. Demographic, hematologic, and clinical features at diagnosis of patients with ET, subdivided according to or CALR mutation status, and of patients with PV ET CALR mutated (A) mutated (B) PV (C) P No (A) vs (B) (B) vs (C) (A) vs (C) Sex (male/female) 90/86 (51%/49%) 167/299 (36%/64%) 233/235 (50%/50%).001, Age at onset, years, median (range) 45 (15-83) 50 (15-92) 57 (13-86).001,.001,.001 Hemoglobin, g/dl, median (range) 13.8 ( ) 14.4 ( ) 18.2 ( ),.001,.001,.001 WBC count, /L, median (range) 8.0 ( ) 9.0 ( ) 10.0 ( ),.001,.001,.001 PLT count, /L, median (range) 883 ( ) 700 ( ) 464 ( ),.001,.001,.001 Serum erythropoietin, mu/ml, median (range) 9.4 (1.2-27) 4.7 (0-47) 2.7 (0-66),.001,.001,.001 Splenomegaly, no. (%) 4(2.3%) 30 (6.4%) 105 (22.4%).046,.001,.001 Lactate dehydrogenase, mu/ml, median (range) 199 (78-472) 200 (77-540) 217 ( ).83, Circulating CD34 1 cells, /L, median (range) 4.1 (0.6-18) 4 (0-15.3) 3.4 ( ) Thrombosis at diagnosis, no. (%) 5(2.8%) 33 (7.1%) 49 (10.5%) Table 2 reports the demographic and clinical characteristics at diagnosis of the patients studied according to their geno, whereas the main hematologic parameters are summarized in Figure 1. Patients with CALR-mutated ET were significantly younger than those with -mutated ET (P )orPV(P,.001). Compared with patients with CALR-mutated ET, those with -mutated ET had higher hemoglobin (Hb) level and white blood cell (WBC) count, and lower platelet (PLT) count and serum erythropoietin (Epo) level (P,.001 in all comparisons). Patients with PV had higher values for Hb level and WBC count, lower values for PLT count and serum Epo, and higher frequency of splenomegaly compared with both CALR- and -mutated ET patients (P values shown in Table 2). The incidence of thrombosis at diagnosis was significantly higher in patients with PV than in those with CALR-mutated ET (P 5.001), but not different between patients with PV and those with -mutated ET (P 5.08). 23 CALR variants Type 1: 46% Type 2: 38% Rumi et al. Blood 2014;123:
10 CALR-mutant ET is a distinct nosolgical entity 25.1% 34.7% 28.6% 10.5% 18% 42% 77% 93% 32% 50% Rumi et al. Blood 2014;123:
11 From by guest on October 3, For personal use only. The impact of CALR mutations on PMF Table 1. Demographic and clinical features at diagnosis of 617 patients with PMF subdivided according to their geno (, CALR,and BLOOD, 14 AUGUST 2014 x VOLUME 124, NUMBER 7 MUTATIONS AND PROGNOSIS OF PRIMARY MYELOFIBROSIS 1063 MPL mutation status) ()-mutant patients mutation. 6 In the current work, we studied a large population of Statistical analysis Type1 CALR mutation is significantly more frequent patients with PMF followed at 4 different centers and analyzed the Numerical variables have been summarized by their median and range, and impact of driver mutations of, CALR, ormpl on clinical categorical variables by count and relative frequency (%) of each category. course, risk ofin leukemic PMF transformation, than and OS. in ET (72% vs 46%, P<.001) Comparisons of quantitative variables between groups of patients were carried out by the nonparametric Wilcoxon rank-sum test. The Wilcoxon signed-rank test was applied to compare measures of quantitative variables repeated in different phases of the disease. Association between categorical variables (2-way tables) was tested by the Fisher exact test. The cumulative Patients and methods incidence of anemia, thrombocytopenia, marked leukocytosis, thrombotic events, and leukemic transformation was estimated with a competing risk This study was approved by the institutional ethics committee (Comitato di approach, considering death for any cause as a competing event. Bioetica, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico 17 The comparison of cumulative incidence curves in different groups of patients was [IRCCS] Policlinico, San Matteo, Pavia, Italy), and by the institutional review carried out using the Pepe-Mori test, boards of the remaining centers. The procedures followed were in accordance 18 whereas the effect of quantitative covariates was estimated by applying the Fine-Gray regression model. with the Helsinki Declaration of 1975, as revised in 2000, and samples were 19 OS was estimated using the Kaplan-Meier product limit method, and survival obtained after patients had provided written informed consent. curves of different subgroups (-mutant, CALR-mutant, MPL-mutant, and triple-negative patients) were compared by the log-rank test. Multivariate Study population and definitions analysis of OS was carried out by Cox regression. Prognostic scores were analyzed as both a fixed and a time-dependent covariate. The Akaike information criterion (AIC) was applied to compare quality of models. 20 Inclusion in the current study required the availability of demographic, clinical, and hematologic data at diagnosis (age, evaluation of constitutional symptoms, hemoglobin level, white blood cell count, and percentage of blasts in peripheral blood) that allow calculation of IPSS, and at least 1 DNA sample to assess mutation status of the 3 driver genes:, MPL, and CALR-mutant patients MPL-mutant patients Patients with nonmutated, CALR, and MPL (triple-negative subjects) No. (%) 399 (64.7%) 140 (22.7%) 25 (4.0%) 53 (8.6%) Sex (male/female) 266/133 77/63 17/8 34/ Age at onset, median (range), y 63 (18-91) 50 (26-83) 64 (31-84) 67 (31-88),.001 Hemoglobin, median (range), g/dl 12 (3-19.6) 11.7 ( ) 11 (6.5-15) 9.9 (5-19),.001 WBC count, median (range), /L 10 ( ) 8.2 (2.2-45) 8.4 ( ) 8.4 ( ).002 PLT count, median (range), /L 310 ( ) 509 ( ) 307 (53-958) 175 ( ),.001 Circulating blasts, median (range), % 0 (0-20) 0 (0-10) 0 (0-4) 0 (0-16),.001 Lactate dehydrogenase, median (range), mu/ml Circulating CD34 1 cells, median (range), /L IPSS risk group, % No. = ( ) 692 ( ) 580 ( ) 531 ( ) ( ) 34.2 ( ) 100 ( ) 45.3 ( ).022 Low ,.001 Intermediate Intermediate High Hb<10g/dl PLT<100x10 9 /l WBC>25x10 9 /l Rumi et al. Blood 2014;124: This criterion provides a measure of the relative goodness of fit of a statistical model and a means for comparison among models, a lower AIC value indicating a better tradeoff between fit andcomplexity. P
12 The impact of CALR mutations on PMF Thrombosis Lower IPSS Leukemic transformation Higher IPSS Rumi et al. Blood 2014;124:
13 , CALR, and MPL mutation status is essential in PMF diagnosis and prognosis 1 CALR+ASXL1- N=46 Median 10.4 years CALR and ASXL1 mutations-based prognosis in myelofibrosis A Tefferi et al Rumi et al. Blood 2014;124: Survival P< CALR-ASXL1+ N=62 Median 2.3 years Years CALR-ASXL1- or CALR+ASXL1+ N=169 Median 5.8 years Tefferi et al. Leukemia 2014;28: Figure 1. Kaplan Meier estimates of overall survival in 277 Mayo Clinic patients with PMF, stratified by the presence or absence of CALR and ASXL1 mutations.
14 Conclusions Accounting for, MPL, and CALR mutation status is of fundamental diagnostic and prognostic relevance in MPN, especially when bone marrow fibrosis is present It also provides a new powerful tool for understanding the molecular basis of MPN, indicating a role of megakaryocytes in the pathogenesis of MPNs
15 Role of megakaryocytes in the pathofisiology of MPN Under normal conditions, MK contribute to the bone marrow matrix environment by expressing fibronectin, IV collagen, and laminin A unifying model of the pathofisiology of MPN implies that the founding driver mutation activates the JAK-STAT pathway in MK, resulting in thrombocytosis initially and in bone marrow fibrosis in the long term Cazzola & Kralovics Blood 2014;123:3714-9
16 Patterns of clonal evolution and phenotypic switch in MPN -pos ET may transform into PV and then progress to smf: % alleles is a major factor in causing the different phenos and 9pUPD is associated with fibrotic evolution MPL mutations are found in ET and PMF; 1pUPD is associated with myelofibrotic transformation CALR ex9 mutations are found in ET and PMF, but 19pUPD seems to be a rare event. Disease evolution is mainly characterised by the progressive expansion of a heterozygous clone that becomes fully dominant in the BM and specifically activates MK Cazzola & Kralovics Blood 2014;123:3714-9
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