RESUMEN
Constitutional mismatch repair deficiency (CMMRD) is an autosomal recessively inherited childhood cancer predisposition syndrome results from biallelic germline mutations affecting the key DNA mismatch repair gene: MLH1, MSH2, MSH6, or PMS2. CMMRD is associated with a high risk of developing early onset of central nervous system tumors, hematologic, and intestinal tract tumors. Clinical manifestations, genetic screening, and cancer prevention strategies are limited. In this report we present a patient with metachronous Wilms tumor, glioblastoma, and acute T-cell lymphoblastic leukemia. He had cutaneous features of neurofibromatosis type 1 (NF1). Molecular testing revealed a novel homozygous mutation in MSH6 (c.2590G>T; p.G864*) that has not been reported previously. CMMRD should be considered in patients with cutaneous features similar to NF1 if tumor is found other than expected tumors in NF, early onset cancer, and strong family history of cancer.
Asunto(s)
Neoplasias Encefálicas/complicaciones , Neoplasias Colorrectales/complicaciones , Proteínas de Unión al ADN/genética , Glioblastoma/patología , Leucemia de Células T/patología , Mutación , Neoplasias Primarias Secundarias/patología , Síndromes Neoplásicos Hereditarios/complicaciones , Tumor de Wilms/patología , Neoplasias Encefálicas/genética , Preescolar , Neoplasias Colorrectales/genética , Resultado Fatal , Glioblastoma/etiología , Homocigoto , Humanos , Neoplasias Renales/etiología , Neoplasias Renales/patología , Leucemia de Células T/etiología , Masculino , Neoplasias Primarias Secundarias/etiología , Síndromes Neoplásicos Hereditarios/genética , Tumor de Wilms/etiologíaRESUMEN
KDM2B together with RING1B, PCGF1, and BCOR or BCORL1 comprise polycomb repressive complex 1.1 (PRC1.1), a noncanonical PRC1 that catalyzes H2AK119ub1. It binds to nonmethylated CpG islands through its zinc finger-CxxC DNA binding domain and recruits the complex to target gene loci. Recent studies identified the loss of function mutations in the PRC1.1 gene, BCOR and BCORL1 in human T-cell acute lymphoblastic leukemia (T-ALL). We previously reported that Bcor insufficiency induces T-ALL in mice, supporting a tumor suppressor role for BCOR. However, the function of BCOR responsible for tumor suppression, either its corepressor function for BCL6 or that as a component of PRC1.1, remains unclear. We herein examined mice specifically lacking the zinc finger-CxxC domain of KDM2B in hematopoietic cells. Similar to Bcor-deficient mice, Kdm2b-deficient mice developed lethal T-ALL mostly in a NOTCH1-dependent manner. A chromatin immunoprecipitation sequence analysis of thymocytes revealed the binding of KDM2B at promoter regions, at which BCOR and EZH2 colocalized. KDM2B target genes markedly overlapped with those of NOTCH1 in human T-ALL cells, suggesting that noncanonical PRC1.1 antagonizes NOTCH1-mediated gene activation. KDM2B target genes were expressed at higher levels than the others and were marked with high levels of H2AK119ub1 and H3K4me3, but low levels of H3K27me3, suggesting that KDM2B target genes are transcriptionally active or primed for activation. These results indicate that PRC1.1 plays a key role in restricting excessive transcriptional activation by active NOTCH1, thereby acting as a tumor suppressor in the initiation of T-cell leukemogenesis.
Asunto(s)
Carcinogénesis/química , Proteínas F-Box/fisiología , Histona Demetilasas con Dominio de Jumonji/fisiología , Leucemia de Células T/etiología , Complejo Represivo Polycomb 1/fisiología , Proteínas Supresoras de Tumor/fisiología , Animales , Islas de CpG , Proteínas F-Box/metabolismo , Histonas , Humanos , Histona Demetilasas con Dominio de Jumonji/deficiencia , Histona Demetilasas con Dominio de Jumonji/metabolismo , Ratones , Mutación , Complejo Represivo Polycomb 1/genética , Complejo Represivo Polycomb 1/metabolismo , Dominios Proteicos , Receptor Notch1/genética , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Activación Transcripcional , Dedos de ZincAsunto(s)
Leucemia de Células T/etiología , Trasplante de Hígado , Trasplante de Pulmón , Complicaciones Posoperatorias/etiología , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Asparaginasa/administración & dosificación , Atresia Biliar/cirugía , Médula Ósea/patología , Ciclofosfamida/administración & dosificación , Citarabina/administración & dosificación , Daunorrubicina/administración & dosificación , Dexametasona/administración & dosificación , Resultado Fatal , Femenino , Herpesvirus Humano 4 , Humanos , Huésped Inmunocomprometido , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Lactante , Leucemia de Células T/tratamiento farmacológico , Leucemia de Células T/patología , Ganglios Linfáticos/patología , Masculino , Mercaptopurina/administración & dosificación , Metotrexato/administración & dosificación , Complicaciones Posoperatorias/tratamiento farmacológico , Complicaciones Posoperatorias/patología , Prednisona/administración & dosificación , Inducción de Remisión , Vincristina/administración & dosificaciónRESUMEN
TAL1/SCL/TCL5 is a critical transcription factor for hematopoietic stem cell maintenance and regulation of early hematopoiesis. However, aberrant expression of TAL1 in committed T-cell precursors is also directly implicated in the development of T-cell leukemia. Roughly 25 years ago TAL1 was identified in early hematopoietic cells and involved in leukemia. Here, we review the wealth of knowledge gained since then on its physiological roles and mechanisms by which TAL1 ectopic expression contributes to leukemogenesis. We emphasize recent findings that shed light into the intricacies of TAL1 (epi)genetic regulation and the transcription network orchestrated by this major T-cell oncogene. Importantly, an exciting time is coming when data using the mechanistic knowledge accumulated on TAL1 may be used to develop novel anti-leukemia targeted therapies.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/fisiología , Leucemia de Células T/etiología , Células Madre Neoplásicas/patología , Proteínas Proto-Oncogénicas/fisiología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Carcinogénesis , Humanos , Leucemia de Células T/genética , Leucemia de Células T/patología , Proteínas Proto-Oncogénicas/genética , Proteína 1 de la Leucemia Linfocítica T AgudaRESUMEN
Mutations in the DYNAMIN2 (DNM2) gene are frequently detected in human acute T-cell lymphoblastic leukemia (T-ALL), although the mechanisms linking these mutations to disease pathogenesis remain unknown. Using an ENU-based forward genetic screen for mice with erythroid phenotypes, we identified a heterozygous mouse line carrying a mutation in the GTPase domain of Dnm2 (Dnm2V265G) that induced a microcytic anemia. In vitro assays using the V265G mutant demonstrated loss of GTPase activity and impaired endocytosis that was comparable to other DNM2 mutants identified in human T-ALL. To determine the effects of DNM2 mutations in T-ALL, we bred the Dnm2V265G mice with the Lmo2 transgenic mouse model of T-ALL. Heterozygous Dnm2 mutants lacking the Lmo2 transgene displayed normal T-cell development, and did not develop T-ALL. In contrast, compound heterozygotes displayed an accelerated onset of T-ALL compared with mice carrying the Lmo2 oncogene alone. The leukemias from these mice exhibited a more immature immunophenotype and an expansion in leukemic stem cell numbers. Mechanistically, the Dnm2 mutation impaired clathrin-mediated endocytosis of the interleukin (IL)-7 receptor resulting in increased receptor density on the surface of leukemic stem cells. These findings suggest that DNM2 mutations cooperate with T-cell oncogenes by enhancing IL-7 signalling.
Asunto(s)
Dinamina II/genética , Interleucina-7/metabolismo , Leucemia de Células T/etiología , Mutación , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Endocitosis/genética , GTP Fosfohidrolasas/metabolismo , Humanos , Proteínas con Dominio LIM/genética , Leucemia de Células T/genética , Leucemia de Células T/metabolismo , Ratones , Oncogenes , Transducción de SeñalRESUMEN
The diagnosis of pyomyositis requires a high index of suspicion in patients with hematologic malignant neoplasms. Correct diagnosis might be delayed initially because of vague clinical presentation, overlapping symptoms, and nonspecific clinical signs. Pyomyositis should be included in the differential diagnosis when a patient develops swollen or tender muscles after chemotherapy with or without bacteremia. Prompt treatment with broad-spectrum antibiotics that cover S aureus and resistant emerging gram-negative organisms, specifically E coli, should be initiated immediately in patients with hematologic illnesses along with close monitoring and follow-up.
Asunto(s)
Celulitis (Flemón)/microbiología , Infecciones por Escherichia coli/microbiología , Leucemia de Células T/etiología , Piomiositis/microbiología , Antibacterianos/uso terapéutico , Celulitis (Flemón)/diagnóstico , Celulitis (Flemón)/tratamiento farmacológico , Niño , Articulación del Codo/patología , Escherichia coli/aislamiento & purificación , Infecciones por Escherichia coli/diagnóstico , Infecciones por Escherichia coli/tratamiento farmacológico , Fiebre/etiología , Humanos , Imagen por Resonancia Magnética , Masculino , Dolor/etiología , Piomiositis/diagnóstico , Piomiositis/tratamiento farmacológico , MusloRESUMEN
Blood smears from a 24-year-old male rhesus macaque ( Macaca mulatta) used for cognitive function studies were evaluated. The macaque had an 8-month history of gradual weight loss and increasing lymphocytosis. Most of the lymphocytes present were small to medium and had a mature morphology. Based on the degree and duration of the lymphocytosis, and the appearance of the lymphocytes, a diagnosis of chronic lymphocytic leukemia was made. The animal tested negative for 4 viral diseases that are commonly associated with lymphoproliferative disorders in Old World monkeys. Over the course of 12 months, the lymphocytosis progressed from 18.4 to 384 × 103 lymphocytes/µl (reference range: 0.8-17 × 103 cells/µl), and euthanasia was elected. On histologic examination, cluster of differentiation (CD)3- and CD8-positive, CD79-negative neoplastic cells comprised 40-60% of the bone marrow, diffusely obscured the normal splenic architecture, and were present in the vascular channels in other organs. Findings were characteristic of T-cell lymphocytic leukemia. Naturally occurring T-cell lymphocytic leukemia has been rarely reported in rhesus macaques and, to the authors' knowledge, never in males. A persistent lymphocytosis characterized by a monomorphic population of CD3- and CD8-positive cytotoxic T-lymphocytes and the presence of neoplastic cells in the bone marrow led to a diagnosis in the current case.
Asunto(s)
Leucemia de Células T/veterinaria , Macaca mulatta , Enfermedades de los Monos/diagnóstico , Animales , Leucemia de Células T/sangre , Leucemia de Células T/diagnóstico , Leucemia de Células T/etiología , Linfocitos/patología , Masculino , Enfermedades de los Monos/sangre , Enfermedades de los Monos/etiologíaAsunto(s)
Síndrome Hipereosinofílico/complicaciones , Leucemia de Células T/etiología , Leucemia de Células T/patología , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Médula Ósea/patología , Progresión de la Enfermedad , Resultado Fatal , Humanos , Síndrome Hipereosinofílico/diagnóstico , Síndrome Hipereosinofílico/tratamiento farmacológico , Inmunofenotipificación , Leucemia de Células T/diagnóstico , Leucemia de Células T/tratamiento farmacológico , MasculinoRESUMEN
Post-translational modifications of Notch3 and their functional role with respect to Notch3 overexpression in T-cell leukemia are still poorly understood. We identify here a specific novel property of Notch3 that is acetylated and deacetylated at lysines 1692 and 1731 by p300 and HDAC1, respectively, a balance impaired by HDAC inhibitors (HDACi) that favor hyperacetylation. By using HDACi and a non-acetylatable Notch3 mutant carrying K/R(1692-1731) mutations in the intracellular domain, we show that Notch3 acetylation primes ubiquitination and proteasomal-mediated degradation of the protein. As a consequence, Notch3 protein expression and its transcriptional activity are decreased both in vitro and in vivo in Notch3 transgenic (tg) mice, thus impairing downstream signaling upon target genes. Consistently, Notch3-induced T-cell proliferation is inhibited by HDACi, whereas it is enhanced by the non-acetylatable Notch3-K/R(1692-1731) mutant. Finally, HDACi-induced Notch3 hyperacetylation prevents in vivo growth of T-cell leukemia/lymphoma in Notch3 tg mice. Together, our findings suggest a novel level of Notch signaling control in which Notch3 acetylation/deacetylation process represents a key regulatory switch, thus representing a suitable druggable target for Notch3-sustained T-cell acute lymphoblastic leukemia therapy.
Asunto(s)
Leucemia de Células T/etiología , Receptores Notch/fisiología , Acetilación , Animales , Células HEK293 , Inhibidores de Histona Desacetilasas/uso terapéutico , Humanos , Leucemia de Células T/tratamiento farmacológico , Activación de Linfocitos , Ratones , Complejo de la Endopetidasa Proteasomal/fisiología , Receptor Notch3 , Linfocitos T/inmunología , UbiquitinaciónRESUMEN
Notch activation is a current event in T Acute Lymphoblastic Leukemia (T-ALL) but the downstream elements that are able to support Notch-dependent leukemias are not well characterized. We have recently shown that the Notch-Hes1-CYLD-NFkB axis is crucial in the maintenance of T-ALL, but detailed evaluation of the contribution of each one of these elements is still missing. Here we use a Notch1-induced leukemia in vivo model to study the effect of silencing the Notch-target gene, Hes1, or over-expressing the Hes1-target, CYLD. We here show that both strategies completely abolish the ability of constitutive active Notch1 to generate T-ALL.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Transformación Celular Neoplásica/genética , Cisteína Endopeptidasas/metabolismo , Proteínas de Homeodominio/metabolismo , Leucemia de Células T/metabolismo , Receptor Notch1/metabolismo , Animales , Línea Celular , Cartilla de ADN/genética , Enzima Desubiquitinante CYLD , Citometría de Flujo , Regulación de la Expresión Génica/fisiología , Humanos , Leucemia de Células T/etiología , Ratones , Ratones Endogámicos C57BL , Receptor Notch1/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Transcripción HES-1 , Transducción GenéticaAsunto(s)
Antineoplásicos/uso terapéutico , Síndrome Hipereosinofílico/etiología , Leucemia de Células T/etiología , Mutación/genética , Proteínas de Fusión Oncogénica/genética , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Factores de Escisión y Poliadenilación de ARNm/genética , Anciano , Benzamidas , Linaje de la Célula , Enfermedad Crónica , Células Clonales , Humanos , Síndrome Hipereosinofílico/patología , Mesilato de Imatinib , Hibridación Fluorescente in Situ , Cariotipificación , Leucemia de Células T/patología , Masculino , Resultado del TratamientoAsunto(s)
Infecciones por HTLV-I/complicaciones , Virus Linfotrópico T Tipo 1 Humano/fisiología , Leucemia de Células T/patología , Leucemia-Linfoma de Células T del Adulto/diagnóstico , Leucemia-Linfoma de Células T del Adulto/etiología , Leucemia-Linfoma de Células T del Adulto/patología , Enfermedades Endémicas/estadística & datos numéricos , Infecciones por HTLV-I/epidemiología , Humanos , Leucemia de Células T/etiología , Masculino , Persona de Mediana Edad , Taiwán/epidemiologíaRESUMEN
Previously, several individuals with X-linked SCID (SCID-X1) were treated by gene therapy to restore the missing IL-2 receptor gamma (IL2RG) gene to CD34+ BM precursor cells using gammaretroviral vectors. While 9 of 10 patients were successfully treated, 4 of the 9 developed T cell leukemia 31-68 months after gene therapy. In 2 of these cases, blast cells contained activating vector insertions near the LIM domain-only 2 (LMO2) proto-oncogene. Here, we report data on the 2 most recent adverse events, which occurred in patients 7 and 10. In patient 10, blast cells contained an integrated vector near LMO2 and a second integrated vector near the proto-oncogene BMI1. In patient 7, blast cells contained an integrated vector near a third proto-oncogene,CCND2. Additional genetic abnormalities in the patients' blast cells included chromosomal translocations, gain-of-function mutations activating NOTCH1, and copy number changes, including deletion of tumor suppressor gene CDKN2A, 6q interstitial losses, and SIL-TAL1 rearrangement. These findings functionally specify a genetic network that controls growth in T cell progenitors. Chemotherapy led to sustained remission in 3 of the 4 cases of T cell leukemia, but failed in the fourth. Successful chemotherapy was associated with restoration of polyclonal transduced T cell populations. As a result, the treated patients continued to benefit from therapeutic gene transfer.
Asunto(s)
Cromosomas Humanos X , Terapia Genética/efectos adversos , Terapia Genética/métodos , Leucemia de Células T/etiología , Inmunodeficiencia Combinada Grave/terapia , Proteínas Adaptadoras Transductoras de Señales , Antineoplásicos/farmacología , Aberraciones Cromosómicas , Ciclina D2 , Ciclinas/genética , Proteínas de Unión al ADN/genética , Gammaretrovirus/metabolismo , Humanos , Lactante , Janus Quinasa 3/genética , Proteínas con Dominio LIM , Leucemia de Células T/complicaciones , Leucemia de Células T/terapia , Metaloproteínas/genética , Modelos Biológicos , Mutación , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas , Receptores de Interleucina-2/genética , Inmunodeficiencia Combinada Grave/complicacionesRESUMEN
Leukemia caused by retroviral insertional mutagenesis after stem cell gene transfer has been reported in several experimental animals and in patients treated for X-linked severe combined immunodeficiency. Here, we analyzed whether gene transfer into mature T cells bears the same genotoxic risk. To address this issue in an experimental "worst case scenario," we transduced mature T cells and hematopoietic progenitor cells from C57BL/6 (Ly5.1) donor mice with high copy numbers of gamma retroviral vectors encoding the potent T-cell oncogenes LMO2, TCL1, or DeltaTrkA, a constitutively active mutant of TrkA. After transplantation into RAG-1-deficient recipients (Ly5.2), animals that received stem cell transplants developed T-cell lymphoma/leukemia for all investigated oncogenes with a characteristic phenotype and after characteristic latency periods. Ligation-mediated polymerase chain reaction analysis revealed monoclonality or oligoclonality of the malignancies. In striking contrast, none of the mice that received T-cell transplants transduced with the same vectors developed leukemia/lymphoma despite persistence of gene-modified cells. Thus, our data provide direct evidence that mature T cells are less prone to transformation than hematopoietic progenitor cells.
Asunto(s)
Transformación Celular Neoplásica/patología , Células Madre Hematopoyéticas/patología , Linfocitos T/patología , Animales , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/metabolismo , Leucemia de Células T/etiología , Linfoma de Células T/etiología , Ratones , Ratones Endogámicos C57BL , Neoplasias Experimentales/etiología , Oncogenes/genética , Transducción GenéticaRESUMEN
We report the first case of T-cell large granular lymphocyte leukemia of donor origin after a second cord blood transplantation for acute myeloid leukemia, and review the literature regarding rare cases of T-cell-origin posttransplantation lymphoproliferative disorders.
Asunto(s)
Donantes de Sangre , Trasplante de Células Madre de Sangre del Cordón Umbilical , Leucemia Mieloide Aguda/terapia , Leucemia de Células T/etiología , Neoplasias Primarias Secundarias/etiología , Trasplante de Células Madre de Sangre del Cordón Umbilical/efectos adversos , Humanos , Japón , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Leucemia de Células T/genética , Leucemia de Células T/patología , Masculino , Persona de Mediana Edad , Neoplasias Primarias Secundarias/genética , Trasplante HomólogoRESUMEN
Previous studies have shown that high levels of MMP-9 can be detected in the serum of patients with various lymphoid malignancies and in leukemia/lymphoma culture supernatants. Indeed, aggressive forms of lymphoma constitutively produce MMP-9 and its elevated levels in the serum or in tissues correlate with advanced stage and poor patient survival. In vitro, MMP-9, which is also produced by the host peritumoral cells in response to the presence of tumors, plays an important role in migration of tumor cells through artificial basement membranes or endothelial cells. In this study, using MMP-9-deficient mice, we show that absence of MMP-9 does not prevent the development of primary T-cell leukemia. Furthermore, MMP-9-deficient cell lines retained their tumorigenic potential, as shown by their ability to induce thymic lymphoma in young syngeneic wild-type animals. In addition, these MMP-9-deficient tumor cells disseminate in normal mice, or mice that are deficient for MMP-9, indicating that tumor growth and dissemination can occur in total absence of MMP-9. These results show for the first time than lymphoma growth can occur in total absence of MMP-9 and have consequences for therapy of invasive cancers with inhibitors of MMPs.
Asunto(s)
Leucemia Inducida por Radiación/enzimología , Leucemia de Células T/enzimología , Linfoma de Células T/enzimología , Metaloproteinasa 9 de la Matriz/deficiencia , Proteínas de Neoplasias/deficiencia , Neoplasias Inducidas por Radiación/enzimología , Neoplasias del Timo/enzimología , Animales , Línea Celular Tumoral/trasplante , Cruzamientos Genéticos , Femenino , Leucemia Inducida por Radiación/patología , Leucemia de Células T/etiología , Linfoma de Células T/etiología , Linfoma de Células T/patología , Masculino , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Invasividad Neoplásica/patología , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/fisiología , Neoplasias Inducidas por Radiación/patología , Organismos Libres de Patógenos Específicos , Neoplasias del Timo/etiología , Neoplasias del Timo/patologíaAsunto(s)
Celulitis (Flemón)/microbiología , Dermatomicosis/etiología , Fusarium , Leucemia de Células T/etiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiología , Trasplante de Células Madre/efectos adversos , Celulitis (Flemón)/patología , Humanos , Leucemia de Células T/complicaciones , Masculino , Persona de Mediana EdadRESUMEN
Signal transduction pathways integrate a variety of microenvironmental cues to guide cell function by regulating gene transcription, cell cycle status, growth, and differentiation. It is well established that perturbation of these processes plays a key role in hematologic malignancies including lymphomas and chronic and acute lymphocytic leukemias. Altered intracellular signaling pathways have been proposed to mediate many biological properties of T cell large granular lymphocytic leukemia (T-LGL), a disorder characterized by a clonal proliferation of CD8 T cells resulting in immune-mediated cytopenias, most commonly neutropenia. Since T-LGL offers a unique opportunity to study signal transduction in the pathologic clonal cytotoxic T cell (CTL) compared to normal CTL, we have investigated a potential imbalance in T-LGL pro-survival signaling to define the mechanisms underlying the semi-autonomous proliferation leading to leukemia. Increased activity of the PI3K-AKT signaling axis in T-LGL cells appears to operate in conjunction with or parallel to increased STAT3 activation in these cells to inhibit the apoptotic program. Thus, the ability to define pathophysiology at the molecular level opens new avenues for targeted therapeutics.
Asunto(s)
Quinasas Janus/metabolismo , Leucemia de Células T/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Factores de Transcripción STAT/metabolismo , Transducción de Señal , Linfocitos T CD8-positivos/inmunología , Humanos , Leucemia de Células T/enzimología , Leucemia de Células T/etiología , Modelos BiológicosRESUMEN
Clonal disorders of large granular lymphocytes (LGLs) represent a spectrum of biologically distinct lymphoproliferative diseases originating either from mature T cells (CD3+) or natural killer (NK) cells (CD3-). Both subtypes, T-cell and NK-cell LGL leukemia, can manifest as indolent or aggressive disorders. The majority of patients with T-cell LGL leukemia have a clinically indolent course with a median survival time >10 years. Immunosuppressive therapy with low-dose methotrexate, cyclophosphamide, or cyclosporine A can control symptoms and cytopenias in more than 50% of patients, but this approach is not curative. Several cases of an aggressive variant (CD3+ CD56+) of T-cell LGL leukemia with a poor prognosis have also been reported. Aggressive NK-cell LGL leukemia is usually a rapidly progressive disorder associated with Epstein-Barr virus (EBV), with a higher prevalence in Asia and South America. This disease is usually refractory to conventional chemotherapy, with a median survival time of 2 months. Chronic NK-cell leukemia/lymphocytosis is a rare EBV-negative disorder with an indolent clinical course. The malignant origin of this subtype is uncertain because clonality is difficult to determine in LGLs of NK-cell origin.