RESUMEN
BACKGROUND: Combined inhibition of phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) complexes may be an efficient treatment for acute leukemia. The primary objective of this phase I single center open label study was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of the dual pan-class I PI3K and mTOR inhibitor BEZ235 in patients with advanced leukemia. METHODS: Herein patients > 18 years of age who had relapsed or showed refractory leukemia were treated with BEZ235 (orally at 300-400 mg BID (cohort - 1/1)) to assess safety, tolerability, preliminary efficacy and pharmacokinetic (PK). Adverse events data and serious adverse events were analyzed and haematological and clinical biochemistry toxicities were assessed from laboratory test parameters. Response was assessed for the first time at the end of cycle 1 (day 29) and after every subsequent cycle. Pharmacokinetic and pharmacodynamic analyses of BEZ235 were also included (BEZ235 plasma levels, phosphorylation of AKT, S6 and 4EBP1). On statistics this trial is a multiple ascending dose study in which a following variant of the 3 + 3 rule ("Rolling Six"), a minimum of 6 and a maximum of 12 patients was recruited for the dose escalation and another 5 were planned for the expansion phase. RESULTS: Twenty-four patients with ALL (n = 11) or AML (n = 12) or CML-BP (n = 1) were enrolled. All patients had failed one (n = 5) or more lines of therapy (n = 5) and 14 patients were in refractory / refractory relapse. No formal MTD was defined, stomatitis and gastrointestinal toxicity at 400 mg BID dose was considered incompatible with prolonged treatment. The RP2D of BEZ235 was defined as 300 mg BID. Four of 24 patients showed clinical benefit. Twenty-two of 24 patients discontinued because of progression, (median time to progression 27 days (4d-112d). There was no association between PK parameters and efficacy or tolerability. CONCLUSIONS: Combined inhibition of PI3K and mTOR inhibits a clinically meaningful driver pathway in a small subset of patients with ALL, with no benefit in patients with AML. TRIAL REGISTRATION: ClinicalTrials.gov , identifier NCT01756118. retrospectively registered 19th December 2012, https://clinicaltrials.gov/ct2/show/NCT01756118 .
Asunto(s)
Antineoplásicos/uso terapéutico , Imidazoles/uso terapéutico , Leucemia/tratamiento farmacológico , Inhibidores de las Quinasa Fosfoinosítidos-3/uso terapéutico , Quinolinas/uso terapéutico , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Resistencia a Antineoplásicos , Femenino , Humanos , Imidazoles/farmacocinética , Imidazoles/farmacología , Leucemia/genética , Leucemia/metabolismo , Masculino , Persona de Mediana Edad , Fosfohidrolasa PTEN/genética , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacocinética , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Quinolinas/farmacocinética , Quinolinas/farmacología , Recurrencia , Proteínas Quinasas S6 Ribosómicas/metabolismo , Factores de Transcripción/genética , Resultado del TratamientoRESUMEN
OBJECTIVES: Randomized comparison of two treatment strategies in frontline therapy of acute promyelocytic leukemia (APL): all-trans retinoic acid (ATRA) and double induction intensified by high-dose cytosine arabinoside (HD ara-C) (German AMLCG) and therapy with ATRA and anthracyclines (Spanish PETHEMA, LPA99). PATIENTS AND RESULTS: Eighty of 87 adult patients with genetically confirmed APL of all risk groups were eligible. The outcome of both arms was similar: AMLCG vs PETHEMA: hematological complete remission 87% vs 83%, early death 13% vs 17% (P = .76), overall survival, event-free survival, leukemia-free survival, cumulative incidence of relapse at 6 years 75% vs 78% (P = .92); 75% vs 68% (P = .29); 86% vs 81% (P = .28); and 0% vs 12% (P = .04, no relapse vs four relapses), respectively. The median time to achieve molecular remission (RT-PCR negativity of PML-RARA) was 60 days in both arms (P = .12). The AMLCG regimen was associated with a longer duration of neutropenia (P = .02) and a higher rate of WHO grade ≥3 infections. CONCLUSIONS: The small number of patients limits the reliability of conclusions. With these restrictions, the outcomes of both approaches were similar and show the limitations of ATRA and chemotherapy. The HD ara-C-containing regimen was associated with a lower relapse rate in high-risk APL.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Promielocítica Aguda/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antraciclinas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores , Quimioterapia de Consolidación , Citarabina/administración & dosificación , Análisis Citogenético , Femenino , Humanos , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/mortalidad , Masculino , Persona de Mediana Edad , Neoplasia Residual/patología , Recurrencia , Inducción de Remisión , Análisis de Supervivencia , Resultado del Tratamiento , Tretinoina/administración & dosificación , Adulto JovenRESUMEN
BACKGROUND CML presenting with a variant Philadelphia translocation, atypical BCR-ABL transcript, additional chromosomal aberrations, and evolving MDS is uncommon and therapeutically challenging. The prognostic significance of these genetic findings is uncertain, even as singular aberrations, with nearly no data on management and outcome when they coexist. MDS evolving during the course of CML may be either treatment-associated or an independently coexisting disease, and is generally considered to have an inferior prognosis. Tyrosine kinase inhibitors (TKI) directed against BCR-ABL are the mainstay of treatment for CML, whereas treatment modalities that may be utilized for MDS and CML include allogeneic stem cell transplant and - at least conceptually - hypomethylating agents. CASE REPORT Here, we describe the clinical course of such a patient, demonstrating that long-term combined treatment with dasatinib and azacitidine for coexisting CML and MDS is feasible and well tolerated, and may be capable of slowing disease progression. This combination therapy had no deleterious effect on subsequent potentially curative haploidentical bone marrow transplantation. CONCLUSIONS The different prognostic implications of this unusual case and new therapeutic options in CML are discussed, together with a review of the current literature on CML presenting with different types of genomic aberrations and the coincident development of MDS. Additionally, this case gives an example of long-term combined treatment of tyrosine kinase inhibitors and hypomethylating agents, which could be pioneering in CML treatment.
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Azacitidina/uso terapéutico , Dasatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Síndromes Mielodisplásicos/terapia , Inhibidores de Proteínas Quinasas/uso terapéutico , Trasplante de Células Madre , Adulto , Quimioterapia Combinada , Femenino , HumanosAsunto(s)
Proteínas de Fusión bcr-abl/genética , Janus Quinasa 2/genética , Mutación , Trastornos Mieloproliferativos/enzimología , Trastornos Mieloproliferativos/genética , Anciano , Anciano de 80 o más Años , Células Clonales , Femenino , Proteínas de Fusión bcr-abl/metabolismo , Humanos , Janus Quinasa 2/metabolismo , Masculino , Persona de Mediana EdadRESUMEN
High BAALC gene expression has been associated with poor prognosis in cytogenetically normal acute myeloid leukaemia (CN-AML) and has been suggested as a suitable marker for assessing minimal residual disease (MRD). The purpose of this study was to substantiate these findings by the analysis of a large data set of 632 diagnostic and follow-up samples in 142 intensively treated CN-AML patients. Paired diagnostic/relapse samples of 35 patients revealed stable high BAALC expression in 89%, irrespective of a high proportion of clonal evolution found in 49% of these cases. High BAALC expression, both directly after induction chemotherapy and within 3-6 months after induction chemotherapy, correlated significantly with shorter event-free survival and overall survival. Moreover, 8 of 10 patients displaying high BAALC expression levels after completion of induction therapy as well as 5 of 5 patients exhibiting high BAALC expression levels within 3-6 months after induction chemotherapy experienced relapse with a median of 197 and 101 days, respectively, from sampling to relapse. Thus, BAALC expression-based MRD detection during therapy may be considered a strategy to identify patients at high risk of relapse.
Asunto(s)
Leucemia Mieloide Aguda/diagnóstico , Proteínas de Neoplasias/genética , Neoplasia Residual/diagnóstico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Estudios de Factibilidad , Femenino , Expresión Génica , Humanos , Cariotipo , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Recurrencia , Inducción de Remisión , Medición de Riesgo/métodos , Tasa de Supervivencia , Adulto JovenRESUMEN
In acute myeloid leukemia (AML), acquired genomic gains and losses are common and lead to altered expression of genes located within or nearby the affected regions. Increased expression of the ETS-related transcription factor gene ERG has been described in myeloid malignancies with chromosomal rearrangements involving chromosome band 21q22, but also in cytogenetically normal AML, where it is associated with adverse prognosis. In this study, fluorescence in situ hybridization on interphase nuclei disclosed an amplification of the ERG gene (more than six copies) in 33 AML patients with structural rearrangements of 21q22. Array comparative genomic hybridization of these cases disclosed a minimal amplified region at the position 39.6-40.0 Mbp from pter that harbors ERG as the only gene. Analysis by quantitative real-time reverse transcription polymerase chain reaction revealed significantly higher ERG mRNA expression in these patients and in a group of 95 AML patients with complete or partial gain of chromosome 21 (three to six copies) compared with 351 AML patients without gain of chromosome 21. Quantification of ERG DNA copy numbers revealed a strong correlation with ERG mRNA expression. Furthermore, in patients with gain of chromosome 21, higher ERG expression was found to be associated with RUNX1 mutations. Our results suggest that acquired gain of chromosome 21 or amplification of chromosome arm 21q is one mechanism contributing to increased ERG expression in AML.
Asunto(s)
Cromosomas Humanos Par 21/genética , Amplificación de Genes , Regulación Neoplásica de la Expresión Génica , Leucemia Mieloide Aguda/genética , Transactivadores/genética , Anciano , Anciano de 80 o más Años , Duplicación Cromosómica , Hibridación Genómica Comparativa , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Regulador Transcripcional ERGRESUMEN
T-cell prolymphocytic leukemia (T-PLL) is a rare post-thymic T-cell neoplasm with aggressive clinical course and short overall survival. So far, due to the rareness of this disease, genetic data are available only from individual cases or small cohorts. In our study, we aimed at performing a comprehensive cytogenetic and molecular genetic characterization of T-PLL comprising the largest cohort of patients with T-PLL analyzed so far, including correlations between the respective markers and their impact on prognosis. Genetic abnormalities were found in all 51 cases with T-PLL, most frequently involving the TCRA/D locus (86%). Deletions were detected for ATM (69%) and TP53 (31%), whereas i(8)(q10) was observed in 61% of cases. Mutations in ATM, TP53, JAK1, and JAK3 were detected in 73, 14, 6, and 21% of patients, respectively. Additionally, BCOR mutations were observed for the first time in a lymphoid malignancy (8%). Two distinct genetic subgroups of T-PLL were identified: A large subset (86% of patients) showed abnormalities involving the TCRA/D locus activating the proto-oncogenes TCL1 or MTCP1, while the second group was characterized by a high frequency of TP53 mutations (4/7 cases). Further, analyses of overall survival identified JAK3 mutations as important prognostic marker, showing a significant negative impact.
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Janus Quinasa 3/genética , Leucemia Prolinfocítica de Células T/genética , Leucemia Prolinfocítica de Células T/patología , Mutación , Adulto , Anciano , Anciano de 80 o más Años , Aberraciones Cromosómicas , Femenino , Variación Genética , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Análisis de Secuencia de ADN , Análisis de SupervivenciaAsunto(s)
Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Mutación , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Proteínas Potenciadoras de Unión a CCAAT/genética , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , ADN (Citosina-5-)-Metiltransferasas/genética , ADN (Citosina-5-)-Metiltransferasas/metabolismo , ADN Metiltransferasa 3A , Análisis Mutacional de ADN , Femenino , Expresión Génica , Perfilación de la Expresión Génica , Humanos , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Nucleofosmina , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Riesgo , Análisis de Supervivencia , Proteínas WT1/genética , Proteínas WT1/metabolismo , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/metabolismoRESUMEN
Germline polymorphisms in genes mutated in acute myeloid leukemia (AML) may have prognostic impact. Therefore, the relevance of the polymorphism IDH1G105 (IDH1105(GGT) minor allele) was evaluated in the context of concomitant molecular mutations in a cohort of 507 AML cases with intermediate-risk cytogenetics. In addition, a cohort of 475 healthy controls was analyzed for this polymorphism. IDH1105(GGT) minor allele was found in 10 % of AML patients and 9 % of healthy controls. While no differences were seen with regard to cytomorphology or cytogenetics, immunophenotyping revealed significantly reduced expression of the progenitor marker CD34 in AML cases harboring IDH1105(GGT) minor allele. Cases with IDH1105(GGT) minor allele as compared to those with the IDH1105(GGC) major allele had significantly longer event-free survival (EFS) (median 16 vs 11 months, p = 0.013) which was most pronounced in the age group >60 years (median 14 vs 9 months, p = 0.007) and in the NPM1 mutated/FLT3-ITD/FLT3wt ratio <0.5 group (median 61 vs 13 months, p = 0.012). However, this association is not independent of other prognostic parameters, and we conclude that IDH1105(GGT) minor allele has to be considered in the context of the genetic background of the individual AML analyzed.
Asunto(s)
Alelos , Biomarcadores de Tumor/genética , Isocitrato Deshidrogenasa/genética , Leucemia Mieloide Aguda , Polimorfismo Genético , Adolescente , Adulto , Anciano , Antígenos CD34 , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Proteínas Nucleares/genética , Nucleofosmina , Tasa de Supervivencia , Tirosina Quinasa 3 Similar a fms/genéticaRESUMEN
In eosinophilia-associated myeloproliferative neoplasms (MPN-eo), constitutive activation of protein tyrosine kinases (TK) as consequence of translocations, inversions, or insertions and creation of TK fusion genes is recurrently observed. The most commonly involved TK and their potential TK inhibitors include PDGFRA at 4q12 or PDGFRB at 5q33 (imatinib), FGFR1 at 8p11 (ponatinib), and JAK2 at 9p24 (ruxolitinib). We here report the identification of three new PDGFRB fusion genes in three male MPN-eo patients: MPRIP-PDGFRB in a case with t(5;17)(q33;p11), CPSF6-PDGFRB in a case with t(5;12)(q33;q15), and GOLGB1-PDGFRB in a case with t(3;5)(q13;q33). The fusion proteins identified by 5'-rapid amplification of cDNA ends polymerase chain reaction (PCR) or DNA-based long distance inverse PCR are predicted to contain the TK domain of PDGFRB. The partner genes contain domains like coiled-coil structures, which are likely to cause dimerization and activation of the TK. In all patients, imatinib induced rapid and durable complete remissions.
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Proteínas Adaptadoras Transductoras de Señales/genética , Eosinofilia/genética , Fusión Génica , Proteínas de la Membrana/genética , Trastornos Mieloproliferativos/genética , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Translocación Genética , Factores de Escisión y Poliadenilación de ARNm/genética , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Cromosomas Humanos Par 12/genética , Cromosomas Humanos Par 17/genética , Cromosomas Humanos Par 3/genética , Cromosomas Humanos Par 5/genética , Análisis Citogenético , Eosinofilia/tratamiento farmacológico , Eosinofilia/patología , Proteínas de la Matriz de Golgi , Humanos , Mesilato de Imatinib/uso terapéutico , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Trastornos Mieloproliferativos/tratamiento farmacológico , Trastornos Mieloproliferativos/patología , Reacción en Cadena de la Polimerasa , Inducción de RemisiónAsunto(s)
Cariotipo Anormal , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicos/genética , Tirosina Quinasa 3 Similar a fms/genética , Proteínas ras/genética , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/patologíaRESUMEN
Since the discovery of the JAK2 V617F mutation in the majority of the myeloproliferative neoplasms (MPN) of polycythemia vera, essential thrombocythemia and primary myelofibrosis ten years ago, further MPN-specific mutational events, notably in JAK2 exon 12, MPL exon 10 and CALR exon 9 have been identified. These discoveries have been rapidly incorporated into evolving molecular diagnostic algorithms. Whilst many of these mutations appear to have prognostic implications, establishing MPN diagnosis is of immediate clinical importance with selection, implementation and the continual evaluation of the appropriate laboratory methodology to achieve this diagnosis similarly vital. The advantages and limitations of these approaches in identifying and quantitating the common MPN-associated mutations are considered herein with particular regard to their clinical utility. The evolution of molecular diagnostic applications and platforms has occurred in parallel with the discovery of MPN-associated mutations, and it therefore appears likely that emerging technologies such as next-generation sequencing and digital PCR will in the future play an increasing role in the molecular diagnosis of MPN.
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Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/genética , Calreticulina/genética , Exones , Humanos , Janus Quinasa 2/genética , Janus Quinasa 2/metabolismo , Técnicas de Diagnóstico Molecular/métodos , Técnicas de Diagnóstico Molecular/normas , Mutación , Trastornos Mieloproliferativos/metabolismo , Garantía de la Calidad de Atención de Salud , Receptores de Trombopoyetina/genéticaRESUMEN
Next generation sequencing technologies have provided insights into the molecular heterogeneity of various myeloid neoplasms, revealing previously unknown somatic genetic events. In our cohort of 1444 cases analyzed by next generation sequencing, somatic mutations in the gene BRCA1-BRCA2-containing complex 3 (BRCC3) were identified in 28 cases (1.9%). BRCC3 is a member of the JAMM/MPN+ family of zinc metalloproteases capable of cleaving Lys-63 linked polyubiquitin chains, and is implicated in DNA repair. The mutations were located throughout its coding region. The average variant allelic frequency of BRCC3 mutations was 30.1%, and by a serial sample analysis at two different time points a BRCC3 mutation was already identified in the initial stage of a myelodysplastic syndrome. BRCC3 mutations commonly occurred in nonsense (n=12), frameshift (n=4), and splice site (n=5) configurations. Due to the marginal male dominance (odds ratio; 2.00, 0.84-4.73) of BRCC3 mutations, the majority of mutations (n=23; 82%) were hemizygous. Phenotypically, BRCC3 mutations were frequently observed in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms and associated with -Y abnormality (odds ratio; 3.70, 1.25-11.0). Clinically, BRCC3 mutations were also related to higher age (P=0.01), although prognosis was not affected. Knockdown of Brcc3 gene expression in murine bone marrow lineage negative, Sca1 positive, c-kit positive cells resulted in 2-fold more colony formation and modest differentiation defect. Thus, BRCC3 likely plays a role as tumor-associated gene in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms.
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Proteínas de la Membrana/genética , Mutación , Trastornos Mieloproliferativos/genética , Anciano , Anciano de 80 o más Años , Alelos , Animales , Proteína BRCA1/genética , Aberraciones Cromosómicas , Análisis Mutacional de ADN , Enzimas Desubicuitinizantes , Femenino , Frecuencia de los Genes , Técnicas de Silenciamiento del Gen , Estudios de Asociación Genética , Genotipo , Humanos , Masculino , Ratones , Persona de Mediana Edad , Trastornos Mieloproliferativos/diagnóstico , Fenotipo , ARN Interferente Pequeño/genéticaRESUMEN
Myeloproliferative neoplasms with eosinophilia are commonly characterized by a normal karyotype and remain poorly defined at the molecular level. We therefore investigated 426 samples from patients with hypereosinophilia of unknown significance initially referred for screening of the FIP1L1-PDGFRA (FP) fusion gene also for KIT D816V and JAK2 V617F mutations. Overall, 86 (20%) patients tested positive: FP+ in 55 (12%), KIT D816V+ in 14 (3%), and JAK2 V617F+ in 17 (4%) patients, respectively. To gain better insight into clinical characteristics, we compared these cases with 31 additional and well-characterized KIT D816V+ eosinophilia-associated systemic mastocytosis (SM-eo) patients enrolled within the "German Registry on Disorders of Eosinophils and Mast cells." Significant differences included younger age, male predominance, and higher eosinophil counts for FP+ cases while abdominal lymphadenopathy, ascites, and serum tryptase levels >100 µg/l were characteristic for those with KIT D816V. Leukocytes, hemoglobin, and splenomegaly did not differ significantly. A median of three additional mutations, most frequently TET2 and SRSF2, were identified in 12/13 KIT D816V+ SM-eo patients with available material indicating a more complex molecular pathogenesis. Median survival was not reached for FP+ cases but was only 26 and 41 months for KIT D816V+ SM and JAK2 V617F+ MPN-eo, respectively. Eosinophilia of ≥2 × 10(9) /l was identified as discriminator for inferior survival in KIT D816V+ and/or JAK2 V617F+ patients (median survival 20 months vs. not reached, P = 0.002). Thus, there is a clear prognostic and therapeutic rationale for detection of KIT D816V and JAK2 V617F in the diagnostic work up of eosinophilia.
Asunto(s)
Síndrome Hipereosinofílico/genética , Janus Quinasa 2/genética , Mastocitosis Sistémica/genética , Mutación , Proteínas Proto-Oncogénicas c-kit/genética , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Sustitución de Aminoácidos , Antineoplásicos/uso terapéutico , Ascitis/patología , Proteínas de Unión al ADN/genética , Dioxigenasas , Femenino , Expresión Génica , Humanos , Síndrome Hipereosinofílico/diagnóstico , Síndrome Hipereosinofílico/tratamiento farmacológico , Síndrome Hipereosinofílico/mortalidad , Enfermedades Linfáticas/patología , Masculino , Mastocitos/patología , Mastocitosis Sistémica/diagnóstico , Mastocitosis Sistémica/tratamiento farmacológico , Mastocitosis Sistémica/mortalidad , Persona de Mediana Edad , Proteínas Nucleares/genética , Proteínas de Fusión Oncogénica/genética , Pronóstico , Proteínas Proto-Oncogénicas/genética , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Recurrencia , Ribonucleoproteínas/genética , Factores de Empalme Serina-Arginina , Factores Sexuales , Análisis de Supervivencia , Triptasas/sangre , Factores de Escisión y Poliadenilación de ARNm/genéticaRESUMEN
Clonal proliferation in myeloproliferative neoplasms (MPN) is driven by somatic mutations in JAK2, CALR or MPL, but the contribution of inherited factors is poorly characterized. Using a three-stage genome-wide association study of 3,437 MPN cases and 10,083 controls, we identify two SNPs with genome-wide significance in JAK2(V617F)-negative MPN: rs12339666 (JAK2; meta-analysis P=1.27 × 10(-10)) and rs2201862 (MECOM; meta-analysis P=1.96 × 10(-9)). Two additional SNPs, rs2736100 (TERT) and rs9376092 (HBS1L/MYB), achieve genome-wide significance when including JAK2(V617F)-positive cases. rs9376092 has a stronger effect in JAK2(V617F)-negative cases with CALR and/or MPL mutations (Breslow-Day P=4.5 × 10(-7)), whereas in JAK2(V617F)-positive cases rs9376092 associates with essential thrombocythemia (ET) rather than polycythemia vera (allelic χ(2) P=7.3 × 10(-7)). Reduced MYB expression, previously linked to development of an ET-like disease in model systems, associates with rs9376092 in normal myeloid cells. These findings demonstrate that multiple germline variants predispose to MPN and link constitutional differences in MYB expression to disease phenotype.
Asunto(s)
Policitemia Vera/genética , Trombocitemia Esencial/genética , Adulto , Anciano , Alelos , Calreticulina/genética , Estudios de Casos y Controles , Estudios de Cohortes , Proteínas de Unión al ADN/genética , Femenino , Proteínas de Unión al GTP/genética , Frecuencia de los Genes , Genes myb/genética , Predisposición Genética a la Enfermedad , Variación Genética , Genotipo , Proteínas HSP70 de Choque Térmico/genética , Humanos , Janus Quinasa 2/genética , Proteína del Locus del Complejo MDS1 y EV11 , Masculino , Persona de Mediana Edad , Mutación , Trastornos Mieloproliferativos/genética , Factores de Elongación de Péptidos/genética , Polimorfismo de Nucleótido Simple , Proto-Oncogenes/genética , Receptores de Trombopoyetina/genética , Telomerasa/genética , Factores de Transcripción/genéticaRESUMEN
The gene CXXC5 on 5q31 is frequently deleted in acute myeloid leukemia (AML) with del(5q), suggesting that inactivation of CXXC5 might play a role in leukemogenesis. Here, we investigated the functional and prognostic implications of CXXC5 expression in AML. CXXC5 mRNA was downregulated in AML with MLL rearrangements, t(8;21) and GATA2 mutations. As a mechanism of CXXC5 inactivation, we found evidence for epigenetic silencing by promoter methylation. Patients with CXXC5 expression below the median level had a lower relapse rate (45% vs 59%; P = .007) and a better overall survival (OS, 46% vs 28%; P < .001) and event-free survival (EFS, 36% vs 21%; P < .001) at 5 years, independent of cytogenetic risk groups and known molecular risk factors. In gene-expression profiling, lower CXXC5 expression was associated with upregulation of cell-cycling genes and co-downregulation of genes implicated in leukemogenesis (WT1, GATA2, MLL, DNMT3B, RUNX1). Functional analyses demonstrated CXXC5 to inhibit leukemic cell proliferation and Wnt signaling and to affect the p53-dependent DNA damage response. In conclusion, our data suggest a tumor suppressor function of CXXC5 in AML. Inactivation of CXXC5 is associated with different leukemic pathways and defines an AML subgroup with better outcome.
Asunto(s)
Proteínas Portadoras/genética , Regulación Leucémica de la Expresión Génica , Leucemia Mieloide Aguda/genética , Mutación/genética , Proteínas Wnt/antagonistas & inhibidores , Adolescente , Adulto , Anciano , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Proteínas Portadoras/antagonistas & inhibidores , Proteínas Portadoras/metabolismo , Ciclo Celular , Estudios de Cohortes , Metilación de ADN , Proteínas de Unión al ADN , Regulación hacia Abajo , Femenino , Estudios de Seguimiento , Perfilación de la Expresión Génica , Humanos , Técnicas para Inmunoenzimas , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Pronóstico , Regiones Promotoras Genéticas/genética , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Tasa de Supervivencia , Factores de Transcripción , Células Tumorales Cultivadas , Adulto JovenAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasia Residual/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Femenino , Humanos , MasculinoRESUMEN
Diagnosis of myelodysplastic syndromes (MDS) relies on well-defined cytomorphologic criteria but is challenging in a significant number of patients. The detection of aberrant antigen expression by multiparameter flow cytometry (MFC) is considered a promising tool to improve MDS diagnostics. We prospectively analyzed 804 unselected patients sent with suspected MDS for correlation of MFC findings with overall survival (OS) in the context of cytomorphologic and cytogenetic findings. Patients with evidence of MDS by MFC had a significantly worse OS as compared to those without (OS at 2 years, 71.2% vs. 89.4%; P<0.001). The number of aberrantly expressed antigens as a continuous variable was significantly associated with OS [P<0.001, hazards ratio (HR): 1.19 per additional aberrantly expressed antigen]. Multivariate analysis proved a diagnosis of MDS by MFC to be independently associated with OS (P=0.050; HR: 1.42). Furthermore, a diagnosis of MDS by MFC was related to inferior survival within all three cytomorphologically defined subgroups, i.e., proven MDS (median OS, 45.4 vs. 52.8 months, P<0.001), suspected MDS (2-year-OS, 75.0% vs. 82.8%; P=0.062), and MDS excluded (2-year-OS, 63.5% vs. 92.8%, P=0.020). Our data clearly demonstrate that, in the assessment of cytopenic patients with suspected MDS, a diagnosis of MDS by MFC is independently associated with OS, which had been shown in previous studies for today's standard diagnostic parameters cytomorphology and cytogenetics. MFC may, therefore, be considered an additional tool in the diagnostic workup of patients with suspected MDS.
Asunto(s)
Antígenos de Neoplasias/genética , Citometría de Flujo/métodos , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antígenos de Neoplasias/inmunología , Niño , Preescolar , Análisis Citogenético , Femenino , Expresión Génica , Humanos , Inmunofenotipificación/métodos , Lactante , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/inmunología , Síndromes Mielodisplásicos/mortalidad , Pronóstico , Estudios Prospectivos , Análisis de SupervivenciaRESUMEN
Preemptive treatment of relapse of acute myeloid leukemia (AML) holds the promise to improve the prognosis of this currently highly lethal condition. Proposed treatment modalities applicable in preemptive cytoreduction (e.g., demethylating agents or standard chemotherapy) differ substantially in interval from administration to antileukemic effect. The t(6;9) balanced translocation, producing the DEK-NUP214 fusion protein, is seen in only 1% of patients with AML. We hypothesized that in these patients, who relapse with a very high frequency, a more detailed knowledge of leukemic relapse growth kinetics would improve the personalized decision-making regarding re-administration of chemotherapy. Based on standardized quantitative PCR data, we therefore delineated the relapse kinetics in a cohort of 27 relapsing DEK-NUP214-positive patients treated in four different European countries. The prerelapse leukemic burden increased with a median doubling time of 13 d (range: 5-51 d, median: 0.71 logs/month, range: 0.18-1.91 logs/month), with FLT3-ITD-positive patients relapsing significantly faster than FLT3-ITD-negative ones (median: 0.9 vs. 0.6 logs/month, Wilcoxon rank sum test, P = 0.041). Peripheral blood and bone marrow were equally useful for minimal residual disease (MRD) detection, and thus, we found that with sampling intervals of 2 months, 94% of relapses would be detected with a median time from MRD detection to hematological relapse of 64 d. In conclusion, this data provide algorithms for handling the rare patients with DEK-NUP214-positive AML allowing for planning of both MRD follow-up and, upon molecular relapse, the timing of cytoreduction or possibly transplant procedures.
Asunto(s)
Algoritmos , Proteínas Cromosómicas no Histona , Leucemia Mieloide Aguda , Modelos Biológicos , Proteínas de Complejo Poro Nuclear , Proteínas de Fusión Oncogénica , Proteínas Oncogénicas , Adolescente , Adulto , Anciano , Niño , Preescolar , Proteínas Cromosómicas no Histona/genética , Proteínas Cromosómicas no Histona/metabolismo , Cromosomas Humanos Par 6/genética , Cromosomas Humanos Par 6/metabolismo , Cromosomas Humanos Par 9/genética , Cromosomas Humanos Par 9/metabolismo , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Cinética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Proteínas de Complejo Poro Nuclear/genética , Proteínas de Complejo Poro Nuclear/metabolismo , Proteínas Oncogénicas/genética , Proteínas Oncogénicas/metabolismo , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Proteínas de Unión a Poli-ADP-Ribosa , Recurrencia , Tasa de Supervivencia , Translocación GenéticaRESUMEN
Trisomy 8 is the most frequent cytogenetically gained aberration in AML. We compared 79 adult de novo AML with trisomy 8 as the sole cytogenetic abnormality (+8sole) to 511 normal karyotype AML patients (NK). +8sole patients were older (p=0.013), presented lower WBC counts (p=0.010), harbored more often ASXL1 mutations (p<0.001) and RUNX1 mutations (p=0.009), but less frequent FLT3-ITD (p=0.038), NPM1 mutations (p<0.001) and double-mutated CEBPA (p=0.038) than NK patients. No prognostic difference was found between +8sole and NK. With respect to genetic stability we found +8sole was instable, and molecular markers were either stable or gained in number and diversity.