RESUMEN
Mutations involving epigenetic regulators (TET2~60% and ASXL1~40%) and splicing components (SRSF2~50%) are frequent in chronic myelomonocytic leukemia (CMML). On a 27-gene targeted capture panel performed on 175 CMML patients (66% males, median age 70 years), common mutations included: TET2 46%, ASXL1 47%, SRSF2 45% and SETBP1 19%. A total of 172 (98%) patients had at least one mutation, 21 (12%) had 2, 24 (14%) had 3 and 30 (17%) had >3 mutations. In a univariate analysis, the presence of ASXL1 mutations (P=0.02) and the absence of TET2 mutations (P=0.03), adversely impacted survival; while the number of concurrent mutations had no impact (P=0.3). In a multivariable analysis that included hemoglobin, platelet count, absolute monocyte count and circulating immature myeloid cells (Mayo model), the presence of ASXL1 mutations (P=0.01) and absence of TET2 mutations (P=0.003) retained prognostic significance. Patients were stratified into four categories: ASXL1wt/TET2wt (n=56), ASXL1mut/TET2wt (n=31), ASXL1mut/TET2mut (n=50) and ASXL1wt/TET2mut (n=38). Survival data demonstrated a significant difference in favor of ASXL1wt/TET2mut (38 months; P=0.016), compared with those with ASXL1wt/TET2wt (19 months), ASXL1mut/TET2wt (21 months) and ASXL1mut/TET2mut (16 months) (P=0.3). We confirm the negative prognostic impact imparted by ASXL1 mutations and suggest a favorable impact from TET2 mutations in the absence of ASXL1 mutations.
Asunto(s)
Proteínas de Unión al ADN/genética , Epistasis Genética , Estudios de Asociación Genética , Leucemia Mielomonocítica Crónica/genética , Leucemia Mielomonocítica Crónica/mortalidad , Mutación , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Dioxigenasas , Femenino , Regulación Leucémica de la Expresión Génica , Frecuencia de los Genes , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Adulto JovenRESUMEN
Although KITD816V occurs universally in adult systemic mastocytosis (SM), the clinical heterogeneity of SM suggests presence of additional phenotype-patterning mutations. Because up to 25% of SM patients have KITD816V-positive eosinophilia, we undertook whole-exome sequencing in a patient with aggressive SM with eosinophilia to identify novel genetic alterations. We conducted sequencing of purified eosinophils (clone/tumor sample), with T-lymphocytes as the matched control/non-tumor sample. In addition to KITD816V, we identified a somatic missense mutation in ethanolamine kinase 1 (ETNK1N244S) that was not present in 50 healthy controls. Targeted resequencing of 290 patients showed ETNK1 mutations to be distributed as follows: (i) SM (n=82; 6% mutated); (ii) chronic myelomonocytic leukemia (CMML; n=29; 14% mutated); (iii) idiopathic hypereosinophilia (n=137; <1% mutated); (iv) primary myelofibrosis (n=32; 0% mutated); and (v) others (n=10; 0% mutated). Of the 82 SM cases, 25 had significant eosinophilia; of these 20% carried ETNK1 mutations. The ten mutations (N244S=6, N244T=1, N244K=1, G245A=2) targeted two contiguous amino acids in the ETNK1 kinase domain, and are predicted to be functionally disruptive. In summary, we identified novel somatic missense ETNK1 mutations that were most frequent in SM with eosinophilia and CMML; this suggests a potential pathogenetic role for dysregulated cytidine diphosphate-ethanolamine pathway metabolites in these diseases.
Asunto(s)
Eosinofilia/genética , Leucemia Mielomonocítica Crónica/genética , Mastocitosis Sistémica/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Adulto , Anciano , Anciano de 80 o más Años , Eosinofilia/complicaciones , Eosinofilia/patología , Exoma/genética , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Leucemia Mielomonocítica Crónica/complicaciones , Leucemia Mielomonocítica Crónica/patología , Masculino , Mastocitosis Sistémica/complicaciones , Mastocitosis Sistémica/patología , Persona de Mediana Edad , MutaciónRESUMEN
In patients with chronic myelomonocytic leukemia (CMML), age>65 years is an adverse prognostic factor. Our objective in the current study was to examine risk factors for survival and treatment outcome in 261 'young' adults with CMML, as defined by age ⩽65 years. In multivariable analysis, lower HB (P=0.01), higher circulating blast % (P=0.002), ASXL1 (P=0.0007) and SRSF2 mutations (P=0.008) and Mayo-French cytogenetic stratification (P=0.04) negatively impacted survival. Similarly, leukemia-free survival was independently affected by higher circulating blast % (P<0.0001), higher bone marrow blast % (P=0.0007) and the presence of circulating immature myeloid cells (P=0.0002). Seventy-five (29%) patients received hypomethylating agents (HMA), with the median number of cycles being 5, and the median duration of therapy being 5 months. The over-all response rate was 40% for azacitidine and 30% for decitabine. Fifty-three (24%) patients underwent an allogeneic hematopoietic stem cell transplant (AHSCT), with a response rate of 56% and a non-relapse mortality of 19%. Survival in young adults with CMML, although higher than in older patients, is poor and even worse in the presence of ASXL1 and SRSF2 mutations. Treatment outcome was more impressive with AHSCT than with HMA and neither was influenced by ASXL1/SRSF2 mutations or karyotype.
Asunto(s)
Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Leucemia Mielomonocítica Crónica/genética , Proteínas Nucleares/genética , Pronóstico , Ribonucleoproteínas/genética , Adulto , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Mielomonocítica Crónica/epidemiología , Leucemia Mielomonocítica Crónica/patología , Masculino , Persona de Mediana Edad , Mutación , Factores de Empalme Serina-Arginina , Resultado del Tratamiento , Adulto JovenRESUMEN
In a cohort of 466 patients, we sought to clarify the prognostic relevance of ASXL1 and SETBP1 mutations, among others, in World Health Organization-defined chronic myelomonocytic leukemia (CMML) and its added value to the Mayo prognostic model. In univariate analysis, survival was adversely affected by ASXL1 (nonsense and frameshift) but not SETBP1 mutations. In multivariable analysis, ASXL1 mutations, absolute monocyte count >10 × 10(9)/l, hemoglobin <10 g/dl, platelets <100 × 10(9)/l and circulating immature myeloid cells were independently predictive of shortened survival: hazard ratio (95% confidence interval (CI)) values were 1.5 (1.1-2.0), 2.2 (1.6-3.1), 2.0 (1.6-2.6), 1.5 (1.2-1.9) and 2.0 (1.4-2.7), respectively. A regression coefficient-based prognostic model based on these five risk factors delineated high (≥3 risk factors; HR 6.2, 95% CI 3.7-10.4) intermediate-2 (2 risk factors; HR 3.4, 95% CI 2.0-5.6) intermediate-1 (one risk factor; HR 1.9, 95% CI 1.1-3.3) and low (no risk factors) risk categories with median survivals of 16, 31, 59 and 97 months, respectively. Neither ASXL1 nor SETBP1 mutations predicted leukemic transformation. The current study confirms the independent prognostic value of nonsense/frameshift ASXL1 mutations in CMML and signifies its added value to the Mayo prognostic model, as had been shown previously in the French consortium model.
Asunto(s)
Proteínas Portadoras/genética , Leucemia Mielomonocítica Crónica/genética , Leucemia Mielomonocítica Crónica/mortalidad , Proteínas Nucleares/genética , Proteínas Represoras/genética , Adulto , Anciano , Anciano de 80 o más Años , Codón sin Sentido , Femenino , Mutación del Sistema de Lectura , Pruebas Genéticas , Humanos , Masculino , Persona de Mediana Edad , Modelos Estadísticos , Análisis Multivariante , Pronóstico , Factores de Riesgo , Análisis de Supervivencia , Adulto JovenRESUMEN
Calreticulin (CALR) mutations were recently described in JAK2 and MPL unmutated primary myelofibrosis (PMF) and essential thrombocythemia. In the current study, we compared the clinical, cytogenetic and molecular features of patients with PMF with or without CALR, JAK2 or MPL mutations. Among 254 study patients, 147 (58%) harbored JAK2, 63 (25%) CALR and 21 (8.3%) MPL mutations; 22 (8.7%) patients were negative for all three mutations, whereas one patient expressed both JAK2 and CALR mutations. Study patients were also screened for ASXL1 (31%), EZH2 (6%), IDH (4%), SRSF2 (12%), SF3B1 (7%) and U2AF1 (16%) mutations. In univariate analysis, CALR mutations were associated with younger age (P<0.0001), higher platelet count (P<0.0001) and lower DIPSS-plus score (P=0.02). CALR-mutated patients were also less likely to be anemic, require transfusions or display leukocytosis. Spliceosome mutations were infrequent (P=0.0001) in CALR-mutated patients, but no other molecular or cytogenetic associations were evident. In multivariable analysis, CALR mutations had a favorable impact on survival that was independent of both DIPSS-plus risk and ASXL1 mutation status (P=0.001; HR 3.4 for triple-negative and 2.2 for JAK2-mutated). Triple-negative patients also displayed inferior LFS (P=0.003). The current study identifies 'CALR(-)ASXL1(+)' and 'triple-negative' as high-risk molecular signatures in PMF.
Asunto(s)
Calreticulina/genética , Janus Quinasa 2/genética , Mutación , Mielofibrosis Primaria/genética , Receptores de Trombopoyetina/genética , Anciano , Anciano de 80 o más Años , Aberraciones Cromosómicas , Análisis Mutacional de ADN , Femenino , Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Mielofibrosis Primaria/diagnóstico , Mielofibrosis Primaria/mortalidad , PronósticoRESUMEN
The majority of patients with BCR-ABL1-negative myeloproliferative neoplasms (MPN) harbor mutations in JAK2 or MPL, which lead to constitutive activation of the JAK/STAT, PI3K and ERK signaling pathways. JAK inhibitors by themselves are inadequate in producing selective clonal suppression in MPN and are associated with hematopoietic toxicities. MK-2206 is a potent allosteric AKT inhibitor that was well tolerated, including no evidence of myelosuppression, in a phase I study of solid tumors. Herein, we show that inhibition of PI3K/AKT signaling by MK-2206 affected the growth of both JAK2V617F- or MPLW515L-expressing cells via reduced phosphorylation of AKT and inhibition of its downstream signaling molecules. Moreover, we demonstrate that MK-2206 synergizes with ruxolitinib in suppressing the growth of JAK2V617F-mutant SET2 cells. Importantly, MK-2206 suppressed colony formation from hematopoietic progenitor cells in patients with primary myelofibrosis and alleviated hepatosplenomegaly and reduced megakaryocyte burden in the bone marrows, livers and spleens of mice with MPLW515L-induced MPN. Together, these findings establish AKT as a rational therapeutic target in the MPNs.
Asunto(s)
Trastornos Mieloproliferativos/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Animales , Apoptosis/efectos de los fármacos , Médula Ósea/metabolismo , Médula Ósea/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Proteínas de Fusión bcr-abl/deficiencia , Compuestos Heterocíclicos con 3 Anillos/farmacología , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Humanos , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 2/genética , Hígado/metabolismo , Hígado/patología , Megacariocitos/efectos de los fármacos , Megacariocitos/metabolismo , Ratones , Mutación , Trastornos Mieloproliferativos/tratamiento farmacológico , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/patología , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/uso terapéutico , Transducción de Señal/efectos de los fármacos , Bazo/efectos de los fármacos , Bazo/metabolismoAsunto(s)
Proteínas Portadoras/genética , Leucemia Mielomonocítica Crónica/genética , Mutación/genética , Proteínas Nucleares/genética , Mielofibrosis Primaria/genética , Anciano , Análisis Mutacional de ADN , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mielomonocítica Crónica/mortalidad , Masculino , Mielofibrosis Primaria/mortalidad , Pronóstico , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tasa de SupervivenciaRESUMEN
We evaluated the prognostic relevance of several clinical and laboratory parameters in 226 Mayo Clinic patients with chronic myelomonocytic leukemia (CMML): 152 (67%) males and median age 71 years. At a median follow-up of 15 months, 166 (73%) deaths and 33 (14.5%) leukemic transformations were documented. In univariate analysis, significant risk factors for survival included anemia, thrombocytopenia, increased levels of white blood cells, absolute neutrophils, absolute monocyte count (AMC), absolute lymphocytes, peripheral blood and bone marrow blasts, and presence of circulating immature myeloid cells (IMCs). Spliceosome component (P=0.4) and ASXL1 mutations (P=0.37) had no impact survival. On multivariable analysis, increased AMC (>10 × 10(9)/l, relative risk (RR) 2.5, 95% confidence interval (CI) 1.7-3.8), presence of circulating IMC (RR 2.0, 95% CI 1.4-2.7), decreased hemoglobin (<10 g/dl, RR 1.6, 99% CI 1.2-2.2) and decreased platelet count (<100 × 10(9)/l, RR 1.4, 99% CI 1.0-1.9) remained significant. Using these four risk factors, a new prognostic model for overall (high risk, RR 4.4, 95% CI 2.9-6.7; intermediate risk, RR 2.0, 95% CI 1.4-2.9) and leukemia-free survival (high risk, RR 4.9, 95% CI 1.9-12.8; intermediate risk, RR 2.6, 95% CI 1.1-5.9) performed better than other conventional risk models and was validated in an independent cohort of 268 CMML patients.
Asunto(s)
Leucemia Mielomonocítica Crónica/genética , Leucemia Mielomonocítica Crónica/mortalidad , Proteínas Represoras/genética , Empalmosomas/genética , Adulto , Anciano , Anciano de 80 o más Años , Anemia/mortalidad , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Modelos Estadísticos , Proteínas Nucleares/genética , Fosfoproteínas/genética , Pronóstico , Factores de Empalme de ARN , Ribonucleoproteína Nuclear Pequeña U2/genética , Ribonucleoproteínas/genética , Factores de Riesgo , Factores de Empalme Serina-Arginina , Factor de Empalme U2AF , Análisis de Supervivencia , Trombocitopenia/mortalidad , Organización Mundial de la Salud , Adulto JovenRESUMEN
Unlike the case with acute myeloid leukemia, there is limited information on the prognostic impact of isocitrate dehydrogenase (IDH) mutations in myelodysplastic syndromes (MDS). In the current study of 277 patients with MDS, IDH mutations were detected in 34 (12%) cases: 26 IDH2 (all R140Q) and 8 IDH1 (6 R132S and 2 R132C). Mutational frequency was 4% (2 of 56) in refractory anemia with ring sideroblasts, 12% (16 of 130) in refractory cytopenia with multilineage dysplasia, 14% (2 of 14) in MDS-unclassifiable, 14% (6 of 42) in refractory anemia with excess blasts (RAEB)-1 and 23% (8 of 35) in RAEB-2. Normal karyotype was noted in all but one IDH1-mutated cases and 13 IDH2-mutated cases. Multivariable analysis identified presence of mutant IDH1 (P=0.0004; hazard ration 4.0, 95% confidence interval 1.9-8.8), revised International Prognostic Scoring System risk category (P<0.0001), and red cell transfusion need (P=0.002) as independent predictors of inferior survival. In a similar multivariable analysis, mutant IDH1 was the only variable associated with shortened leukemia-free survival (P=0.001; hazard ration 7.0, 95% confidence interval 2.3-20.8). The presence of IDH2R140Q did not affect the overall (P=0.54) or leukemia-free (P=0.81) survival. The current study suggests a powerful adverse prognostic effect for mutant IDH1 in MDS.
Asunto(s)
Isocitrato Deshidrogenasa/genética , Mutación , Síndromes Mielodisplásicos/patología , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Bases , Cartilla de ADN , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Síndromes Mielodisplásicos/enzimología , Síndromes Mielodisplásicos/genética , Pronóstico , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Isocitrate dehydrogenase (IDH) mutations are frequent in blast-phase myeloproliferative neoplasms and might therefore contribute to leukemic transformation. We examined this possibility in 301 consecutive patients with chronic-phase primary myelofibrosis (PMF). The mutant IDH was detected in 12 patients (4%): 7 IDH2 (5 R140Q, 1 R140W and 1 R172G) and 5 IDH1 (3 R132S and 2 R132C). In all, 6 (50%) of the 12 IDH-mutated patients also expressed JAK2V617F. Overall, 18 (6%) patients displayed only MPL and 164 (54.3%) only JAK2 mutations. Multivariable analysis that accounted for conventional risk factors disclosed inferior overall survival (OS; P=0.03) and leukemia-free survival (LFS; P=0.003) in IDH-mutated patients: OS hazard ratio (HR) was 0.39 (95% confidence interval (95% CI) 0.2-0.75), 0.50 (95% CI 0.27-0.95) and 0.53 (95% CI 0.23-1.2) for patients with no, JAK2 or MPL mutations, respectively. Further analysis disclosed a more pronounced effect for the mutant IDH on OS and LFS in the presence (P=0.0002 and P<0.0001, respectively) as opposed to the absence (P=0.34 and P=0.64) of concomitant JAK2V617F. Analysis of paired samples obtained during chronic- and blast-phase disease revealed the presence of both IDH and JAK2 mutations at both time points. Our observations suggest that IDH mutations in PMF are independent predictors of leukemic transformation and raise the possibility of leukemogenic collaboration with JAK2V617F.
Asunto(s)
Transformación Celular Neoplásica/genética , Epistasis Genética , Isocitrato Deshidrogenasa/genética , Janus Quinasa 2/genética , Mutación , Mielofibrosis Primaria/genética , Mielofibrosis Primaria/mortalidad , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Receptores de Trombopoyetina/genética , Análisis de Supervivencia , Adulto JovenAsunto(s)
Péptidos y Proteínas de Señalización Intracelular/genética , Isocitrato Deshidrogenasa/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mieloide Aguda/genética , Mutación/genética , Polimorfismo Genético/genética , Alelos , Genotipo , Glioma/genética , Humanos , ARN Largo no Codificante , Factores de RiesgoRESUMEN
MPL and JAK2V617F mutation analysis was performed in 603 patients with primary myelofibrosis (PMF) seen at the Mayo Clinic, USA (n=329) or University of Florence, Italy (n=274). Mutant MPL was detected in 49 (8.1%) patients and JAK2V617F in 350 (58%); 4 patients showed both mutations. MPLW515L/K was the commonest mutation; 2 patients showed novel mutations (L513ins and Q516-P518insAAAA). The US and Italy patient cohorts were separately analyzed for comparison of survival and clinical features between MPL-mutated, JAK2-mutated and JAK2/MPL-unmutated cases. JAK2/MPL-unmutated patients were significantly younger than their JAK2-mutated counterparts, in both patient cohorts (P<0.01). In the Florence only cohort, the presence of mutant MPL was associated with older age (P<0.01) and constitutional symptoms (P=0.04) and JAK2V617F with higher hemoglobin (P<0.01) and leukocyte (P=0.03) count; neither patient cohort showed significant associations with platelet count, hemoglobin <10 g/dl, abnormal/unfavorable karyotype, spleen size or prognostic score distribution. To date, 240 deaths and 79 leukemic transformations have been documented among all 603 study patients. Multivariable analysis disclosed no significant difference in overall or leukemia-free survival between the three molecular subgroups. We conclude that the presence of mutant MPL has narrow and inconsistent phenotypic effect in PMF and does not influence overall or leukemia-free survival.
Asunto(s)
Mutación/genética , Mielofibrosis Primaria/genética , Mielofibrosis Primaria/mortalidad , Receptores de Trombopoyetina/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Italia , Janus Quinasa 2/genética , Cariotipo , Masculino , Persona de Mediana Edad , Pronóstico , Tasa de Supervivencia , Estados Unidos , Adulto JovenRESUMEN
The 2008 World Health Organization (WHO) criteria were used to identify 88 consecutive Mayo Clinic patients with 'myelodysplastic syndrome with isolated del(5q)' (median age 74 years; 60 females). In all, 60 (68%) patients were followed up to the time of their death. Overall median survival was 66 months; leukemic transformation was documented in five (5.7%) cases. Multivariable analysis identified age >or=70 years (P=0.01), transfusion need at diagnosis (P=0.04) and dysgranulopoiesis (P=0.02) as independent predictors of shortened survival; the presence of zero (low risk), one (intermediate risk) or >or=2 (high risk) risk factors corresponded to median survivals of 102, 52 and 27 months, respectively. Janus kinase 2 (JAK2), thrombopoietin receptor (MPL), isocitrate dehydrogenase 1 (IDH1) and IDH2 mutational analysis was performed on archived bone marrows in 78 patients; JAK2V617F and MPLW515L mutations were shown in five (6.4%) and three (3.8%) patients, respectively, and did not seem to affect phenotype or prognosis. IDH mutations were not detected. Survival was not affected by serum ferritin and there were no instances of death directly related to iron overload. The current study is unique in its strict adherence to WHO criteria for selecting study patients and providing information on long-term survival, practical prognostic factors, baseline risk of leukemic transformation and the prevalence of JAK2, MPL and IDH mutations.
Asunto(s)
Cromosomas Humanos Par 5/genética , Isocitrato Deshidrogenasa/genética , Janus Quinasa 2/genética , Mutación/genética , Síndromes Mielodisplásicos/genética , Receptores de Trombopoyetina/genética , Adulto , Anciano , Anciano de 80 o más Años , Transformación Celular Neoplásica , Deleción Cromosómica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/patología , Reacción en Cadena de la Polimerasa , Pronóstico , Tasa de Supervivencia , Organización Mundial de la SaludRESUMEN
In a multi-institutional collaborative project, 1473 patients with myeloproliferative neoplasms (MPN) were screened for isocitrate dehydrogenase 1 (IDH1)/IDH2 mutations: 594 essential thrombocythemia (ET), 421 polycythemia vera (PV), 312 primary myelofibrosis (PMF), 95 post-PV/ET MF and 51 blast-phase MPN. A total of 38 IDH mutations (18 IDH1-R132, 19 IDH2-R140 and 1 IDH2-R172) were detected: 5 (0.8%) ET, 8 (1.9%) PV, 13 (4.2%) PMF, 1 (1%) post-PV/ET MF and 11 (21.6%) blast-phase MPN (P<0.01). Mutant IDH was documented in the presence or absence of JAK2, MPL and TET2 mutations, with similar mutational frequencies. However, IDH-mutated patients were more likely to be nullizygous for JAK2 46/1 haplotype, especially in PMF (P=0.04), and less likely to display complex karyotype, in blast-phase disease (P<0.01). In chronic-phase PMF, JAK2 46/1 haplotype nullizygosity (P<0.01; hazard ratio (HR) 2.9, 95% confidence interval (CI) 1.7-5.2), but not IDH mutational status (P=0.55; HR 1.3, 95% CI 0.5-3.4), had an adverse effect on survival. This was confirmed by multivariable analysis. In contrast, in both blast-phase PMF (P=0.04) and blast-phase MPN (P=0.01), the presence of an IDH mutation predicted worse survival. The current study clarifies disease- and stage-specific IDH mutation incidence and prognostic relevance in MPN and provides additional evidence for the biological effect of distinct JAK2 haplotypes.
Asunto(s)
Isocitrato Deshidrogenasa/genética , Mutación/genética , Policitemia Vera/genética , Mielofibrosis Primaria/genética , Trombocitemia Esencial/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Crisis Blástica , Estudios de Cohortes , Femenino , Humanos , Janus Quinasa 2/genética , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Pronóstico , Receptores de Trombopoyetina/genética , Adulto JovenRESUMEN
Bone marrow DNA was screened for isocitrate dehydrogenase (IDH) mutations in 200 patients with chronic (n=166) or blast (n=34) phase myeloproliferative neoplasms (MPN). Included among the former were 77 patients with primary myelofibrosis (PMF), 47 essential thrombocythemia and 38 polycythemia vera (PV). Nine IDH mutations (5 IDH1 and 4 IDH2) were detected; mutational frequencies were approximately 21% (7 of 34) for blast-phase MPN and approximately 4% (3 of 77) for PMF. IDH mutations were seen in only 1 of 12 paired chronic-blast-phase samples and in none of 27 concurrently studied acute myeloid leukemia (AML) patients without antecedent MPN. IDH1 mutations included R132C (n=4; two post-PMF AML, one post-PV AML and one PMF) and R132S (n=1; post-PMF AML). IDH2 mutations included R140Q (n=3; one post-PMF AML, one post-PV AML and one PMF) and a novel R140W (n=1; mutation found in both chronic- and blast-phase samples). The entire study cohort was also screened for JAK2 and MPL mutations and JAK2V617F was found in three IDH-mutated cases (two PMF and one PV). This study shows a relatively high incidence of IDH mutations in blast-phase MPN, regardless of JAK2 mutational status, and the occurrence of similar mutations in chronic-phase PMF.