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1.
Blood Adv ; 3(3): 339-349, 2019 02 12.
Artículo en Inglés | MEDLINE | ID: mdl-30709865

RESUMEN

Somatic TET2 mutations (TET2 MT) are frequent in myeloid neoplasia (MN), particularly chronic myelomonocytic leukemia (CMML). TET2 MT includes mostly loss-of-function/hypomorphic hits. Impaired TET2 activity skews differentiation of hematopoietic stem cells toward proliferating myeloid precursors. This study was prompted by the observation of frequent biallelic TET2 gene inactivations (biTET2 i ) in CMML. We speculated that biTET2 i might be associated with distinct clinicohematological features. We analyzed TET2 MT in 1045 patients with MN. Of 82 biTET2 i cases, 66 were biTET2 MT, 13 were hemizygous TET2 MT, and 3 were homozygous TET2 MT (uniparental disomy); the remaining patients (denoted biTET2 - hereafter) were either monoallelic TET2 MT (n = 96) or wild-type TET2 (n = 823). Truncation mutations were found in 83% of biTET2 i vs 65% of biTET2 - cases (P = .02). TET2 hits were founder lesions in 72% of biTET2 i vs 38% of biTET2 - cases (P < .0001). In biTET2 i , significantly concurrent hits included SRSF2 MT (33%; P < .0001) and KRAS/NRAS MT (16%; P = .03) as compared with biTET2 - When the first TET2 hit was ancestral in biTET2 i , the most common subsequent hits affected a second TET2 MT, followed by SRSF2 MT, ASXL1 MT, RAS MT, and DNMT3A MT BiTET2 i patients without any monocytosis showed an absence of SRSF2 MT BiTET2 i patients were older and had monocytosis, CMML, normal karyotypes, and lower-risk disease compared with biTET2 - patients. Hence, while a second TET2 hit occurred frequently, biTET2 i did not portend faster progression but rather determined monocytic differentiation, consistent with its prevalence in CMML. Additionally, biTET2 i showed lower odds of cytopenias and marrow blasts (≥5%) and higher odds of myeloid dysplasia and marrow hypercellularity. Thus, biTET2 i might represent an auxiliary assessment tool in MN.


Asunto(s)
Proteínas de Unión al ADN/genética , Síndromes Mielodisplásicos/genética , Proteínas Proto-Oncogénicas/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Proteínas de Unión al ADN/metabolismo , Dioxigenasas , Femenino , Silenciador del Gen , Humanos , Masculino , Persona de Mediana Edad , Mutación , Síndromes Mielodisplásicos/sangre , Síndromes Mielodisplásicos/patología , Fenotipo , Pronóstico , Proteínas Proto-Oncogénicas/metabolismo , Adulto Joven
3.
Leukemia ; 33(3): 612-624, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30209403

RESUMEN

Leukemic relapse is frequently accompanied by progressively aggressive clinical course. To understand the molecular mechanism of leukemic relapse, MLL/AF9-transformed mouse leukemia cells were serially transplanted in C57BL/6 mice (N = 96) by mimicking repeated recurrences, where mutations were monitored by exome sequencing (N = 42). The onset of leukemia was progressively promoted with advanced transplants, during which increasing numbers of somatic mutations were acquired (P < 0.005). Among these, mutations in Ptpn11 (p.G60R) and Braf (p.V637E) corresponded to those identified in human MLL-AML, while recurrent mutations affecting Msn (p.R295C) were observed only in mouse but not in human MLL-AML. Another mutated gene of interest was Gnb2 which was reported to be recurrently mutated in various hematological neoplasms. Gnb2 mutations (p.G77R) were significantly increased in clone size (P = 0.007) and associated with earlier leukemia onset (P = 0.011). GNB2 transcripts were significantly upregulated in human MLL-AML compared to MLL-negative AML (P < 0.05), which was supported by significantly increased Gnb2 transcript induced by MLL/AF9 overexpression (P < 0.001). In in vivo model, both mutation and overexpression of GNB2 caused leukemogenesis, and downregulation of GNB2 expression reduced proliferative potential and survival benefit, suggesting a driver role of GNB2. In conclusion, alterations of driver genes over time may play an important role in the progression of MLL-AML.


Asunto(s)
N-Metiltransferasa de Histona-Lisina/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Proteína de la Leucemia Mieloide-Linfoide/genética , Animales , Proliferación Celular/genética , Progresión de la Enfermedad , Regulación hacia Abajo/genética , Proteínas de Unión al GTP/genética , Regulación Leucémica de la Expresión Génica/genética , Humanos , Ratones , Ratones Endogámicos C57BL , Mutación/genética , Proteínas de Fusión Oncogénica/genética , Regulación hacia Arriba/genética
5.
Leukemia ; 32(8): 1751-1761, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29795413

RESUMEN

Somatic mutations in TET2 are common in myelodysplastic syndromes (MDS), myeloproliferative, and overlap syndromes. TET2 mutant (TET2MT) clones are also found in asymptomatic elderly individuals, a condition referred to as clonal hematopoiesis of indeterminate potential (CHIP). In various entities of TET2MT neoplasia, we examined the phenotype in relation to the strata of TET2 hits within the clonal hierarchy. Using deep sequencing, 1781 mutations were found in 1205 of 4930 patients; 40% of mutant cases were biallelic. Hierarchical analysis revealed that of TET2MT cases >40% were ancestral, e.g., representing 8% of MDS. Higher (earlier) TET2 lesion rank within the clonal hierarchy (greater clonal burden) was associated with impaired survival. Moreover, MDS driven by ancestral TET2MT is likely derived from TET2MT CHIP with a penetrance of ~1%. Following ancestral TET2 mutations, individual disease course is determined by secondary hits. Using multidimensional analyses, we demonstrate how hits following the TET2 founder defect induces phenotypic shifts toward dysplasia, myeloproliferation, or progression to AML. In summary, TET2MT CHIP-derived MDS is a subclass of MDS that is distinct from de novo disease.


Asunto(s)
Células Clonales/patología , Proteínas de Unión al ADN/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Mutación , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/patología , Proteínas Proto-Oncogénicas/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Estudios de Casos y Controles , Diferenciación Celular , Evolución Clonal , Células Clonales/metabolismo , Dioxigenasas , Progresión de la Enfermedad , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Humanos , Persona de Mediana Edad , Pronóstico
7.
Oncotarget ; 9(2): 2050-2057, 2018 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-29416752

RESUMEN

Using next generation sequencing we have systematically analyzed a large cohort of 489 patients with bone marrow failure (BMF), including myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), aplastic anemia (AA), and related conditions for the presence of germline (GL) alterations in Fanconi Anemia (FA) and telomerase genes. We have detected an increased frequency of heterozygous FA gene mutations in MDS and to lesser degree in AML suggesting that the presence of one normal allele may not be completely protective and indeed heterozygous FA lesions may have a long latency period before hematologic manifestation. In contrast, GL telomerase gene mutations were not associated with increased disease risk. When compared to large control cohorts, we have not detected an increased frequency of damaging variants among telomerase complex genes, including those previously believed to be involved in the pathogenesis of AA. Our results may suggest that while low penetrance and delayed disease onset can confound identification of genetic predisposition factors, GL FA alterations can be also associated with MDS.

8.
Blood Cancer J ; 8(1): 4, 2018 01 10.
Artículo en Inglés | MEDLINE | ID: mdl-29321554

RESUMEN

Intermediate-risk acute myeloid leukemia (IR-AML) is a clinically heterogeneous disease, for which optimal post-remission therapy is debated. The utility of next-generation sequencing information in decision making for IR-AML has yet to be elucidated. We retrospectively studied 100 IR-AML patients, defined by European Leukemia Net classification, who had mutational information at diagnosis, received intensive chemotherapy and achieved complete remission (CR) at Cleveland Clinic (CC). The Cancer Genome Atlas (TCGA) data were used for validation. In the CC cohort, median age was 58.5 years, 64% had normal cytogenetics, and 31% required >1 induction cycles to achieve CR1. In univariable analysis, patients carrying mutations in DNMT3A, U2AF1, and EZH2 had worse overall and relapse-free survival. After adjusting for other variables, the presence of these mutations maintained an independent effect on survival in both CC and TCGA cohorts. Patients who did not have the mutations and underwent hematopoietic cell transplant (HCT) had the best outcomes. HCT improved outcomes for patients who had these mutations. RUNX1 or ASXL1 mutations did not predict survival, and performance of HCT did not confer a significant survival benefit. Our results provide evidence of clinical utility in considering mutation screening to stratify IR-AML patients after CR1 to guide therapeutic decisions.


Asunto(s)
ADN (Citosina-5-)-Metiltransferasas/genética , Proteína Potenciadora del Homólogo Zeste 2/genética , Leucemia Mieloide Aguda , Factor de Empalme U2AF/genética , Adulto , Anciano , ADN Metiltransferasa 3A , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Mutación , Estudios Prospectivos , Factores de Riesgo , Tasa de Supervivencia
9.
Haematologica ; 103(2): 221-230, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-29217782

RESUMEN

Pure red cell aplasia is an orphan disease, and as such lacks rationally established standard therapies. Most cases are idiopathic; a subset is antibody-mediated. There is overlap between idiopathic cases and those with T-cell large granular lymphocytic leukemia, hypogammaglobulinemia, and low-grade lymphomas. In each of the aforementioned, the pathogenetic mechanisms may involve autoreactive cytotoxic responses. We selected 62 uniformly diagnosed pure red cell aplasia patients and analyzed their pathophysiologic features and responsiveness to rationally applied first-line and salvage therapies in order to propose diagnostic and therapeutic algorithms that may be helpful in guiding the management of prospective patients, 52% of whom were idiopathic, while the others involved large granular lymphocytic leukemia, thymoma, and B-cell dyscrasia. T-cell-mediated responses ranged between a continuum from polyclonal to monoclonal (as seen in large granular lymphocytic leukemia). During a median observation period of 40 months, patients received a median of two different therapies to achieve remission. Frequently used therapy included calcineurin-inhibitors with a steroid taper yielding a first-line overall response rate of 76% (53/70). Oral cyclophosphamide showed activity, albeit lower than that produced by cyclosporine. Intravenous immunoglobulins were effective both in parvovirus patients and in hypogammaglobulinemia cases. In salvage settings, alemtuzumab is active, particularly in large granular lymphocytic leukemia-associated cases. Other potentially useful salvage options include rituximab, anti-thymocyte globulin and bortezomib. The workup of acquired pure red cell aplasia should include investigations of common pathological associations. Most effective therapies are directed against T-cell-mediated immunity, and therapeutic choices need to account for associated conditions that may help in choosing alternative salvage agents, such as intravenous immunoglobulin, alemtuzumab and bortezomib.


Asunto(s)
Algoritmos , Manejo de la Enfermedad , Aplasia Pura de Células Rojas/terapia , Terapia Recuperativa/métodos , Adulto , Anciano , Anciano de 80 o más Años , Alemtuzumab/uso terapéutico , Antineoplásicos/uso terapéutico , Bortezomib/uso terapéutico , Femenino , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Estudios Retrospectivos
10.
Leuk Lymphoma ; 59(2): 416-422, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-28633612

RESUMEN

Large granular lymphocytic leukemia (LGLL) represents a clonal/oligoclonal lymphoproliferation of cytotoxic T and natural killer cells often associated with STAT3 mutations. When symptomatic, due to mostly anemia and neutropenia, therapy choices are often empirically-based, because only few clinical trials and systematic studies have been performed. Incorporating new molecular and flow cytometry parameters, we identified 204 patients fulfilling uniform criteria for LGLL diagnoses and analyzed clinical course with median follow-up of 36 months, including responses to treatments. While selection of initial treatment was dictated by clinical features, the initial responses, as well as overall responses to methotrexate (MTX), cyclosporine (CsA), and cyclophosphamide (CTX), were similar at 40-50% across drugs. Sequential use of these drugs resulted in responses in most cases: only 10-20% required salvage therapies such as ATG, Campath, tofacitinib, splenectomy or abatacept. MTX yielded the most durable responses. STAT3-mutated patients required therapy more frequently and had better overall survival.


Asunto(s)
Leucemia Linfocítica Granular Grande/diagnóstico , Leucemia Linfocítica Granular Grande/mortalidad , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunofenotipificación , Leucemia Linfocítica Granular Grande/genética , Leucemia Linfocítica Granular Grande/terapia , Masculino , Persona de Mediana Edad , Mutación , Pronóstico , Receptores de Antígenos de Linfocitos T/genética , Factor de Transcripción STAT3/genética , Análisis de Supervivencia , Evaluación de Síntomas , Resultado del Tratamiento
13.
Haematologica ; 102(6): 1028-1034, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28255022

RESUMEN

Myelodysplastic syndromes are typically diseases of older adults. Patients in whom the onset is early may have distinct molecular and clinical features or reflect a demographic continuum. The identification of differences between "early onset" patients and those diagnosed at a traditional age has the potential to advance understanding of the pathogenesis of myelodysplasia and may lead to formation of distinct morphological subcategories. We studied a cohort of 634 patients with various subcategories of myelodysplastic syndrome and secondary acute myeloid leukemia, stratifying them based on age at presentation and clinical parameters. We then characterized molecular abnormalities detected by next-generation deep sequencing of 60 genes that are commonly mutated in myeloid malignancies. The number of mutations increased linearly with age and on average, patients >50 years of age had more mutations. TET2, SRSF2, and DNMT3A were more commonly mutated in patients >50 years old compared to patients ≤50 years old. In general, patients >50 years of age also had more mutations in spliceosomal, epigenetic modifier, and RAS gene families. Although there are age-related differences in molecular features among patients with myelodysplasia, most notably in the incidence of SRSF2 mutations, our results suggest that patients ≤50 years old belong to a disease continuum with a distinct pattern of early onset ancestral events.


Asunto(s)
Edad de Inicio , Mutación , Síndromes Mielodisplásicos/genética , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , ADN (Citosina-5-)-Metiltransferasas/genética , ADN Metiltransferasa 3A , Análisis Mutacional de ADN , Proteínas de Unión al ADN/genética , Dioxigenasas , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas/genética , Factores de Empalme Serina-Arginina/genética , Adulto Joven
14.
J Exp Med ; 214(3): 753-771, 2017 03 06.
Artículo en Inglés | MEDLINE | ID: mdl-28232469

RESUMEN

Despite the identification of several oncogenic driver mutations leading to constitutive JAK-STAT activation, the cellular and molecular biology of myeloproliferative neoplasms (MPN) remains incompletely understood. Recent discoveries have identified underlying disease-modifying molecular aberrations contributing to disease initiation and progression. Here, we report that deletion of Nol3 (Nucleolar protein 3) in mice leads to an MPN resembling primary myelofibrosis (PMF). Nol3-/- MPN mice harbor an expanded Thy1+LSK stem cell population exhibiting increased cell cycling and a myelomonocytic differentiation bias. Molecularly, this phenotype is mediated by Nol3-/--induced JAK-STAT activation and downstream activation of cyclin-dependent kinase 6 (Cdk6) and MycNol3-/- MPN Thy1+LSK cells share significant molecular similarities with primary CD34+ cells from PMF patients. NOL3 levels are decreased in CD34+ cells from PMF patients, and the NOL3 locus is deleted in a subset of patients with myeloid malignancies. Our results reveal a novel genetic PMF-like mouse model and identify a tumor suppressor role for NOL3 in the pathogenesis of myeloid malignancies.


Asunto(s)
Proteínas Reguladoras de la Apoptosis/fisiología , Proteínas Musculares/fisiología , Proteínas Supresoras de Tumor/fisiología , Animales , Proteínas Reguladoras de la Apoptosis/genética , Línea Celular Tumoral , Hematopoyesis Extramedular/fisiología , Humanos , Quinasas Janus/fisiología , Ratones , Ratones Endogámicos C57BL , Proteínas Musculares/genética , Mielofibrosis Primaria/etiología , Factor de Transcripción STAT3/fisiología , Transducción de Señal
15.
Nat Genet ; 49(2): 204-212, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-27992414

RESUMEN

To elucidate differential roles of mutations in myelodysplastic syndromes (MDS), we investigated clonal dynamics using whole-exome and/or targeted sequencing of 699 patients, of whom 122 were analyzed longitudinally. Including the results from previous reports, we assessed a total of 2,250 patients for mutational enrichment patterns. During progression, the number of mutations, their diversity and clone sizes increased, with alterations frequently present in dominant clones with or without their sweeping previous clones. Enriched in secondary acute myeloid leukemia (sAML; in comparison to high-risk MDS), FLT3, PTPN11, WT1, IDH1, NPM1, IDH2 and NRAS mutations (type 1) tended to be newly acquired, and were associated with faster sAML progression and a shorter overall survival time. Significantly enriched in high-risk MDS (in comparison to low-risk MDS), TP53, GATA2, KRAS, RUNX1, STAG2, ASXL1, ZRSR2 and TET2 mutations (type 2) had a weaker impact on sAML progression and overall survival than type-1 mutations. The distinct roles of type-1 and type-2 mutations suggest their potential utility in disease monitoring.


Asunto(s)
Evolución Clonal/genética , Síndromes Mielodisplásicos/genética , Células Clonales/metabolismo , Progresión de la Enfermedad , Exoma/genética , Humanos , Leucemia Mieloide Aguda/genética , Mutación/genética , Nucleofosmina
16.
Int J Hematol ; 101(3): 213-8, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25690487

RESUMEN

Whole exome next generation sequencing systematically applied as a discovery tool in myelodysplastic syndromes (MDS) has led to the identification of a large number of novel mutations. Despite hundreds of patients studied, mutational saturation has not been reached and it is expected that new driver mutations will be discovered in this very heterogeneous condition. Serial samples and deep sequencing of the identified alterations has allowed for a dynamic/chronologic analysis of clonal architecture and identification of a subset of ancestral and secondary molecular lesions. Chromosomal gains and losses have been incorporated into the mutational analyses because they can either cooperate with mutations or produce a functional phenocopy. In addition to the search for somatic defects in MDS, similar discovery studies have been also performed to identify germ line mutations/alterations. Clinical analysis showed applicability of multiplexed somatic mutational panels that would complement current pathomorphologic diagnosis, allow for subclassification of nosologic entities, and enhance predictive power of current prognostic algorithms. Overall, comprehensive genomic analysis in MDS has revealed a tremendous heterogeneity of somatic lesions and their combinations further enhanced by the heterogeneity of clonal architecture and chromosomal lesions.


Asunto(s)
Mutación , Síndromes Mielodisplásicos/genética , Trastornos Mieloproliferativos/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Síndromes Mielodisplásicos/diagnóstico , Trastornos Mieloproliferativos/diagnóstico , Pronóstico
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