RESUMEN
We investigated using a custom NGS panel of 149 genes the mutational landscape of 64 consecutive adult patients with tyrosine kinase fusion-negative hypereosinophilia (HE)/hypereosinophilic syndrome (HES) harboring features suggestive of myeloid neoplasm. At least one mutation was reported in 50/64 (78%) patients (compared to 8/44 (18%) patients with idiopathic HE/HES/HEUS used as controls; p < .001). Thirty-five patients (54%) had at least one mutation involving the JAK-STAT pathway, including STAT5B (n = 18, among which the hotspot N642H, n = 13), JAK1 (indels in exon 13, n = 5; V658F/L, n = 2), and JAK2 (V617F, n = 6; indels in exon 13, n = 2). Other previously undescribed somatic mutations were also found in JAK2, JAK1, STAT5B, and STAT5A, including three patients who shared the same STAT5A V707fs mutation and features consistent with primary polycythemia. Nearly all JAK-STAT mutations were preceded by (or associated with) myelodysplasia-related gene mutations, especially in RNA-splicing genes or chromatin modifiers. In multivariate analysis, neurologic involvement (hazard ratio [HR] 4.95 [1.87-13.13]; p = .001), anemia (HR 5.50 [2.24-13.49]; p < .001), and the presence of a high-risk mutation (as per the molecular international prognosis scoring system: HR 6.87 [2.39-19.72]; p < .001) were independently associated with impaired overall survival. While corticosteroids were ineffective in all treated JAK-STAT-mutated patients, ruxolitinib showed positive hematological responses including in STAT5A-mutated patients. These findings emphasize the usefulness of NGS for the workup of tyrosine kinase fusion-negative HE/HES patients and support the use of JAK inhibitors in this setting. Updated classifications could consider patients with JAK-STAT mutations and eosinophilia as a new "gene mutated-entity" that could be differentiated from CEL, NOS, and idiopathic HES.
Asunto(s)
Síndrome Hipereosinofílico , Mutación , Factor de Transcripción STAT5 , Humanos , Síndrome Hipereosinofílico/genética , Síndrome Hipereosinofílico/tratamiento farmacológico , Masculino , Femenino , Persona de Mediana Edad , Adulto , Anciano , Factor de Transcripción STAT5/genética , Janus Quinasa 2/genética , Transducción de Señal , Janus Quinasa 1/genética , Anciano de 80 o más Años , Pirimidinas/uso terapéutico , Adulto JovenRESUMEN
Myeloproliferative neoplasms, mastocytosis, myeloid/lymphoid neoplasms with hypereosinophilia and tyrosine kinase gene fusions, and myelodysplastic/myeloproliferative neoplasms are clonal hematopoietic cancers that, with the exception of certain entities, have an indolent course. In addition to their increasingly important role in the diagnosis of these entities, as shown by the recent classification of hematolymphoid tumors in the 5th edition of the World Health Organization and the International Consensus Classification of myeloid neoplasms and acute leukemias, identification of the profile of acquired genetic abnormalities is essential for adapting patient management and early detection of patients at high risk of progression. Alongside molecular abnormalities, cytogenetic abnormalities play an important role in the diagnosis, prognosis and follow-up of these diseases. Here, we review the recent literature on the impact of chromosomal abnormalities in these different entities and provide updated cytogenetic recommendations and guidelines for their management.
Asunto(s)
Hematología , Mastocitosis , Trastornos Mieloproliferativos , Humanos , Aberraciones Cromosómicas , Análisis Citogenético , Mastocitosis/diagnóstico , Mastocitosis/genética , Mastocitosis/terapia , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/terapia , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/terapiaAsunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva , Leucemia Mielomonocítica Crónica , Leucemia Mielomonocítica Juvenil , Proteínas de Fusión bcr-abl/genética , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielomonocítica Crónica/genéticaAsunto(s)
Mutación de Línea Germinal , Factor de Transcripción PAX5/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Adulto , Niño , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Linaje , Leucemia-Linfoma Linfoblástico de Células Precursoras B/congénito , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologíaAsunto(s)
Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Femenino , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/fisiología , Humanos , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológicoAsunto(s)
Proteínas de Unión al ADN/genética , Mutación del Sistema de Lectura , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Leucemia Mieloide Aguda/genética , Leucemia Mielomonocítica Crónica/genética , Linfoma de Células T/genética , Proteínas Proto-Oncogénicas/genética , Anciano , Dioxigenasas , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/terapia , Leucemia Mielomonocítica Crónica/patología , Leucemia Mielomonocítica Crónica/terapia , Linfoma de Células T/patología , Linfoma de Células T/terapia , Masculino , Persona de Mediana Edad , Linaje , PronósticoAsunto(s)
Cromosomas Humanos X/genética , Isocromosomas , Leucemia Mieloide/genética , Síndromes Mielodisplásicos/genética , Distribución por Edad , Anciano , Médula Ósea/patología , Cromosomas Humanos X/ultraestructura , Proteínas de Unión al ADN/genética , Dioxigenasas , Femenino , Estudios de Seguimiento , Genes Relacionados con las Neoplasias , Humanos , Leucemia Mieloide/epidemiología , Leucemia Mieloide/patología , Masculino , Persona de Mediana Edad , Mutación , Síndromes Mielodisplásicos/epidemiología , Síndromes Mielodisplásicos/patología , Proteínas de Neoplasias/genética , Neoplasias Primarias Secundarias/genética , Neoplasias Primarias Secundarias/patología , Proteínas Proto-Oncogénicas/genética , Distribución por SexoAsunto(s)
Anticuerpos Monoclonales/efectos adversos , Antígenos CD19/inmunología , Reordenamiento Génico , N-Metiltransferasa de Histona-Lisina/genética , Inmunoterapia/efectos adversos , Leucemia Mieloide Aguda/patología , Proteína de la Leucemia Mieloide-Linfoide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Femenino , Humanos , Leucemia Mieloide Aguda/inducido químicamente , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , PronósticoRESUMEN
Clonal chromosome abnormalities in Philadelphia-negative cells could concern chronic myeloid leukemia patients treated by tyrosine kinase inhibitors. The European LeukemiaNet distinguishes -7/del(7q) abnormalities as a "warning". However, the impact of clonal chromosome abnormalities, and specifically those of -7/del(7q), in Philadelphia-negative cells on clinical outcomes is unclear and based on case-reports showing morphological dysplasia and increased risk of acute myeloid leukemia, suggesting the coexistence of chronic myeloid leukemia and high-risk myelodysplastic syndrome. The aim of this study was to determine whether the impact of -7/del(7q) clonal chromosome abnormalities in Philadelphia-negative cells on the clinical outcome is different from that of other types of abnormalities, and we argue for an underlying associated high-risk myelodysplastic syndrome. Among 102 chronic myeloid leukemia patients with clonal chromosome abnormalities in Philadelphia-negative cells with more than a median of 6 years of follow up, patients with -7/del(7q) more frequently had signs of dysplasia, a lower cumulative incidence of deep molecular response and often needed further treatment lines, with the consequent impact on event-free and progression-free survival. Morphological features of dysplasia are associated with myelodysplastic syndrome/acute myeloid leukemia mutations and compromise the optimal response to tyrosine kinase inhibitors, irrespectively of the type of clonal chromosome abnormalities in Philadelphia-negative cells. However, mutation patterns determined by next-generation sequencing could not clearly explain the underlying high-risk disease. We hereby confirm the pejorative prognostic value of -7/del(7q) clonal chromosome abnormalities in Philadelphia-negative cells and suggest that myelodysplastic features constitute a warning signal that response to tyrosine kinase inhibitors may be less than optimal.
Asunto(s)
Aberraciones Cromosómicas , Cromosomas Humanos Par 7 , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/etiología , Metafase/genética , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/genética , Alelos , Deleción Cromosómica , Progresión de la Enfermedad , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Hibridación Fluorescente in Situ , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Mutación , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/terapia , Pronóstico , Análisis de SupervivenciaRESUMEN
BACKGROUND: The ultimate goal of chronic myeloid leukemia management in the tyrosine kinase inhibitor (TKI) era for patients who obtain deep molecular responses is maintaining a durable off-treatment response after treatment discontinuation; this situation is called treatment-free remission (TFR). Knowledge accumulated during the last 10 years justifies moving TFR strategies from research to clinical practice. METHODS: Twenty experts from the French Chronic Myeloid Leukemia Study Group (France Intergroupe des Leucémies Myéloïdes Chroniques), including 17 hematologists, 2 molecular biologists, and 1 cytogeneticist, critically reviewed published data with the goal of developing evidence-based recommendations for TKI discontinuation in clinical practice. RESULTS: Clinically relevant questions were addressed, including the selection of candidate patients (with known prognostic factors for outcomes taken into account), detailed monitoring procedures during the treatment-free phase, a definition of relapse requiring therapy resumption, and monitoring after treatment reintroduction. CONCLUSIONS: This work presents consensus statements with the aim of guiding physicians and biologists by means of pragmatic recommendations for safe TKI discontinuation in daily practice. Cancer 2018;124:2956-63. © 2018 American Cancer Society.
Asunto(s)
Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Hematología/normas , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Oncología Médica/normas , Recurrencia Local de Neoplasia/diagnóstico , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Factores de Edad , Consenso , Francia , Proteínas de Fusión bcr-abl/sangre , Proteínas de Fusión bcr-abl/aislamiento & purificación , Proteínas de Fusión bcr-abl/metabolismo , Hematología/métodos , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/sangre , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Oncología Médica/métodos , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/prevención & control , Educación del Paciente como Asunto , Selección de Paciente , Pronóstico , Inducción de Remisión/métodos , Resultado del Tratamiento , Espera Vigilante/normas , Adulto JovenRESUMEN
Approximately 30% of the patients who fulfil the criteria of Waldenström's macroglobulinemia (WM) are diagnosed while asymptomatic (indolent), and will not require immediate therapy. Conversely, patients with a disease-related event will be considered for therapy. The physiopathology of these 2 groups remains unclear, and the mechanisms of progression from indolent to symptomatic WM have yet to be fully understood. Seventeen patients diagnosed with WM were included in this study, 8 asymptomatic WM (A-WM) and 9 symptomatic WM (S-WM). A differential analysis was performed on a first series of 11 patients and identified 48 genes whose expression separated samples from A- to S-WM. This gene signature was then confirmed on a second independent validation set of 6 WM. Within this expression profile, BACH2, a B-cell transcription factor known to be a tumor suppressor gene, was found to be over-expressed in A-MW relatively to S-MW. We specifically over-expressed BACH2 in a WM-related cell line and observed a significant reduction of the clonogenic activity. To the best of our knowledge, we report for the first time a specific gene expression signature that differentiates A-WM and S-WM. Within this expression profile, BACH2 was identified as a candidate gene that may help to understand better the behavior of tumor cells in indolent WM.
RESUMEN
Purpose:TP53 is a tumor-suppressor gene that functions as a regulator influencing cellular responses to DNA damage, and TP53 alterations are associated with pejorative outcome in most B-lymphoid disorders. Little is known regarding TP53 alteration in Waldenstrom's macroglobulinemia (WM).Experimental Design: Here, we have explored the incidence of TP53 alteration using Sanger sequencing and ultradeep-targeted sequencing in 125 WM and 10 immunoglobulin M (IgM) monoclonal gammopathy of undetermined significance (MGUS), along with the clinical features and the associated genomic landscape using single-nucleotide polymorphism array and mutational landscape in an integrative study.Results: Overall, we have identified alteration of TP53 locus including mutation, deletion, and copy-neutral LOH in 11.2% of WM. TP53 mutation was acquired in 7.3% of patients with WM at diagnosis, being absent in IgM MGUS, and was highly correlated to deletion 17p. No correlation with CXCR4 mutations was observed. Patients with TP53 alteration had a greater number of genomic abnormalities. Importantly, WM with TP53 alteration had a significantly shorter overall survival, particularly in symptomatic WM, and independently of the international prognostic scoring system for Waldenstrom macroglobulinemia (IPSSWM) score. Specific treatment for WM with TP53 may have to be studied. Nutlin-3a-targeted p53 signaling induced cytotoxicity preclinically, along with new compounds such as ibrutinib, PrimaMet, or CP31398 that bypass p53 pathway in WM, paving the path for future treatment-tailored options.Conclusions: Our results highlight the clinical significance of detection of TP53 alteration in WM to determine the prognosis of WM and guide the treatment choice. Clin Cancer Res; 23(20); 6325-35. ©2017 AACR.
Asunto(s)
Mutación , Proteína p53 Supresora de Tumor/genética , Macroglobulinemia de Waldenström/diagnóstico , Macroglobulinemia de Waldenström/genética , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis , Supervivencia Celular/genética , Deleción Cromosómica , Cromosomas Humanos Par 17 , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Unión Proteica , Dominios y Motivos de Interacción de Proteínas/genética , Análisis de Supervivencia , Proteína p53 Supresora de Tumor/química , Proteína p53 Supresora de Tumor/metabolismo , Macroglobulinemia de Waldenström/mortalidadRESUMEN
Multiple myeloma (MM) is a frequently incurable hematological cancer in which overactivity of MYC plays a central role, notably through up-regulation of ribosome biogenesis and translation. To better understand the oncogenic program driven by MYC and investigate its potential as a therapeutic target, we screened a chemically diverse small-molecule library for anti-MM activity. The most potent hits identified were rocaglate scaffold inhibitors of translation initiation. Expression profiling of MM cells revealed reversion of the oncogenic MYC-driven transcriptional program by CMLD010509, the most promising rocaglate. Proteome-wide reversion correlated with selective depletion of short-lived proteins that are key to MM growth and survival, most notably MYC, MDM2, CCND1, MAF, and MCL-1. The efficacy of CMLD010509 in mouse models of MM confirmed the therapeutic relevance of these findings in vivo and supports the feasibility of targeting the oncogenic MYC-driven translation program in MM with rocaglates.
Asunto(s)
Mieloma Múltiple/genética , Mieloma Múltiple/terapia , Animales , Línea Celular Tumoral , Ciclina D1/genética , Humanos , Ratones , Proteínas Proto-Oncogénicas c-maf/genética , Proteínas Proto-Oncogénicas c-myc/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Wilm's tumor, aniridia, genitourinary anomalies, and mental retardation (WAGR) syndrome, a rare genetic disorder, is caused by the loss of 11p13 region including PAX6 and WT1. We report novel findings in a 28-month-old boy with aniridia, Wilm's tumor, congenital hypothyroidism, and sublingual thyroid ectopia. He was found to have a mosaic 5.28 Mb interstitial deletion of chromosome 11p13 deleting PAX6 and WT1. In order to clarify the mechanism underlying his thyroid dysgenesis, sequence analysis of candidate thyroid developmental genes was performed. We identified a FOXE1: c.532_537delGCCGCC p.(Ala178_Ala179del) variant that predisposes to thyroid ectopia. Taken together, this is the first report of mosaic 11p13 deletion in association with thyroid dysgenesis. We also propose a model of complex interactions of different genetic variants for this particular phenotype in the present patient.
Asunto(s)
Hipotiroidismo Congénito/genética , Factores de Transcripción Forkhead/genética , Disgenesias Tiroideas/genética , Síndrome WAGR/genética , Preescolar , Deleción Cromosómica , Cromosomas Humanos Par 11 , Hipotiroidismo Congénito/fisiopatología , Humanos , Hibridación Fluorescente in Situ , Masculino , Mosaicismo , Factor de Transcripción PAX6/genética , Fenotipo , Disgenesias Tiroideas/fisiopatología , Síndrome WAGR/fisiopatología , Proteínas WT1/genéticaRESUMEN
Cytogenetic evaluation is one the most important criteria for diagnosis and response to treatment in chronic myeloid leukemia, and recent baseline prognostic factors including particular additional clonal cytogenetic abnormalities have been established. The French cytogenetic group in hematology GFCH proposes here an updating of recommendations for cytogenetic assessment of CML in the era of tyrosine kinase inhibitors.
Asunto(s)
Análisis Citogenético/normas , Hematología/normas , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Aberraciones Cromosómicas , Análisis Citogenético/métodos , Análisis Citogenético/tendencias , Francia , Hematología/organización & administración , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Monitoreo Fisiológico/métodos , Monitoreo Fisiológico/normas , Sociedades Médicas , Translocación GenéticaRESUMEN
CD81 is a cell surface protein which belongs to the tetraspanin family. While in multiple myeloma its expression on plasma cells is associated with worse prognosis, this has not yet been explored in acute myeloid leukemia (AML). We measured membrane expression of CD81 on AML cells at diagnosis, evaluated its association with AML characteristics and its influence on patient outcome after intensive chemotherapy in a cohort of 134 patients. CD81 was detected in 92/134 (69%) patients. Patients with AML expressing CD81 had elevated leukocyte count (P=0.02) and were more likely classified as intermediate or adverse-risk by cytogenetics (P<0.001). CD81 expression had a negative impact on survival (event-free survival, overall survival and relapse-free survival) in univariate (P<0.001) and in multivariate analyses (P=0.003, 0.002 and <0.001, respectively). CD81 has a negative impact on OS in patients with NPM1 mutation (P=0.01) and in patients ELN-favorable (P=0.002). In conclusion, this cell surface marker may be a new prognostic marker for diagnostic risk classification and a potential therapeutic target for drug development in AML.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Tetraspanina 28/metabolismo , Adulto , Factores de Edad , Anciano , Membrana Celular/metabolismo , Supervivencia sin Enfermedad , Femenino , Citometría de Flujo , Estudios de Seguimiento , Células Precursoras de Granulocitos/metabolismo , Células Precursoras de Granulocitos/ultraestructura , Humanos , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/sangre , Leucemia Mieloide Aguda/genética , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Mutación , Proteínas Nucleares/genética , Nucleofosmina , Pronóstico , Adulto JovenRESUMEN
We report a case of myeloproliferative neoplasm (MPN) with an atypical t(9;22;15)(p24;q11;q21) translocation, leading to a BCR-JAK2 fusion, associated with a trisomy of chromosome 8 in clonal evolution at karyotype. Patient's evolution was marked by an aggressive clinical course with rapid progression to blast phase within the first year after diagnosis. Examination of matched chronic phase and blast crisis samples by SNP-array karyotyping identified secondary acquired cryptic genetic events at the time of lymphoblastic transformation, including biallelic IKZF1 alteration and EBF1 and CDKN2A/B codeletions. This case is the first report describing acquisition of secondary genetic events leading to acute lymphoblastic progression in a rare MPN with BCR-JAK2 fusion.
Asunto(s)
Transformación Celular Neoplásica/genética , Janus Quinasa 2/genética , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/patología , Proteínas de Fusión Oncogénica , Proteínas Proto-Oncogénicas c-bcr/genética , Translocación Genética , Bandeo Cromosómico , Progresión de la Enfermedad , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Análisis de Secuencia de ADNRESUMEN
Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct cytogenetic subgroup of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with poor prognosis that should be investigated in routine practice. Single-nucleotide polymorphism (SNP)-array provides a useful method to detect such cases showing a highly characteristic profile.