RESUMO
ABSTRACT: Adult T-cell leukemia/lymphoma (ATL) is triggered by infection with human T-cell lymphotropic virus-1 (HTLV-1). Here, we describe the reprogramming of pyrimidine biosynthesis in both normal T cells and ATL cells through regulation of uridine-cytidine kinase 2 (UCK2), which supports vigorous proliferation. UCK2 catalyzes the monophosphorylation of cytidine/uridine and their analogues during pyrimidine biosynthesis and drug metabolism. We found that UCK2 was overexpressed aberrantly in HTLV-1-infected T cells but not in normal T cells. T-cell activation via T-cell receptor (TCR) signaling induced expression of UCK2 in normal T cells. Somatic alterations and epigenetic modifications in ATL cells activate TCR signaling. Therefore, we believe that expression of UCK2 in HTLV-1-infected cells is induced by dysregulated TCR signaling. Recently, we established azacitidine-resistant (AZA-R) cells showing absent expression of UCK2. AZA-R cells proliferated normally in vitro, whereas UCK2 knockdown inhibited ATL cell growth. Although uridine and cytidine accumulated in AZA-R cells, possibly because of dysfunction of pyrimidine salvage biosynthesis induced by loss of UCK2 expression, the amount of UTP and CTP was almost the same as in parental cells. Furthermore, AZA-R cells were more susceptible to an inhibitor of dihydroorotic acid dehydrogenase, which performs the rate-limiting enzyme of de novo pyrimidine nucleotide biosynthesis, and more resistant to dipyridamole, an inhibitor of pyrimidine salvage biosynthesis, suggesting that AZA-R cells adapt to UCK2 loss by increasing de novo pyrimidine nucleotide biosynthesis. Taken together, the data suggest that fine-tuning pyrimidine biosynthesis supports vigorous cell proliferation of both normal T cells and ATL cells.
Assuntos
Vírus Linfotrópico T Tipo 1 Humano , Pirimidinas , Adulto , Humanos , Uridina/metabolismo , Proliferação de Células , Citidina , Nucleotídeos de Pirimidina , Receptores de Antígenos de Linfócitos T , Linfócitos T/metabolismoRESUMO
The recent evolution of molecular targeted therapy has improved clinical outcomes in several human malignancies. The translocation of anaplastic lymphoma kinase (ALK) was originally identified in anaplastic large-cell lymphoma (ALCL) and subsequently in non-small cell lung carcinoma (NSCLC). Since ALK fusion gene products act as a driver of carcinogenesis in both ALCL and NSCLC, several ALK tyrosine kinase inhibitors (TKIs) have been developed. Crizotinib and alectinib are first- and second-generation ALK TKIs, respectively, approved for the treatment of ALK-positive ALCL (ALK+ ALCL) and ALK+ NSCLC. Although most ALK+ NSCLC patients respond to crizotinib and alectinib, they generally relapse after several years of treatment. We previously found that DNA-demethylating agents enhanced the efficacy of ABL TKIs in chronic myeloid leukemia cells. Moreover, aberrant DNA methylation has also been observed in ALCL cells. Thus, to improve the clinical outcomes of ALK+ ALCL therapy, we investigated the synergistic efficacy of the combination of alectinib and the DNA-demethylating agent azacytidine, decitabine, or OR-2100 (an orally bioavailable decitabine derivative). As expected, the combination of alectinib and DNA-demethylating agents synergistically suppressed ALK+ ALCL cell proliferation, concomitant with DNA hypomethylation and a reduction in STAT3 (a downstream target of ALK fusion proteins) phosphorylation. The combination of alectinib and OR-2100 markedly altered gene expression in ALCL cells, including that of genes implicated in apoptotic signaling, which possibly contributed to the synergistic anti-ALCL effects of this drug combination. Therefore, alectinib and OR-2100 combination therapy has the potential to improve the outcomes of patients with ALK+ ALCL.
RESUMO
Cronkhite-Canada syndrome (CCS) is a rare polyposis disorder accompanied by alopecia and onychodystrophy. A 63-year-old man with a history of CCS and repeated embolism developed progressive thrombocytopenia and mild anemia. Laboratory testing, a bone marrow examination, and magnetic resonance imaging of the spine resulted in a diagnosis of concurrent aplastic anemia (AA). Paroxysmal nocturnal hemoglobinuria (PNH)-type cells were detected in a peripheral blood specimen. In addition, human leukocyte antigen (HLA) included DRB1*15:01 and DRB1*15:02. Mesalazine was discontinued in consideration of possible drug-induced pancytopenia. Immunosuppressive therapy ameliorated both the gastrointestinal symptoms of CCS and pancytopenia. A common autoimmune abnormality might underlie both CCS and AA.
Assuntos
Anemia Aplástica , Hemoglobinúria Paroxística , Polipose Intestinal , Anemia Aplástica/complicações , Anemia Aplástica/diagnóstico , Hemoglobinúria Paroxística/complicações , Hemoglobinúria Paroxística/diagnóstico , Antígenos de Histocompatibilidade Classe I , Humanos , Polipose Intestinal/complicações , Polipose Intestinal/diagnóstico , Masculino , Mesalamina , Pessoa de Meia-IdadeRESUMO
Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) is an aggressive leukemia that occurs in 20-40% of adult patients. Ph + ALL is caused by the Philadelphia chromosome (Ph), which consists of a t(9;22)(q34;q11) reciprocal translocation leading to the formation of a BCR-ABL1 fusion gene. The disease is treated with targeted therapy comprising ABL1 tyrosine kinase inhibitors (TKIs). Ponatinib is a third generation TKI that demonstrates higher binding affinity for ABL1 than first/second generation TKIs. Although intensive combined immunotherapy with ponatinib greatly improves the prognosis of Ph + ALL, the safety and efficacy profiles of ponatinib in Japanese patients are unclear. This retrospective study investigated five cases of Ph + ALL at a single institute to evaluate safety and efficacy profiles. Three patients achieved a deep molecular response (DMR) following combined intensive treatment with ponatinib as induction chemotherapy. Four patients received consolidative allogenic stem cell transplantation (allo-SCT) during their first complete response. Three of the four experienced early relapse within 100 days; they subsequently received ponatinib, and one of the three achieved a DMR. No patient experienced severe cardiovascular events. This case series suggests that ponatinib at a concentration of least 30 mg exhibits anti-leukemia effects in Japanese patients with Ph + ALL.
Assuntos
Proteínas de Fusão bcr-abl/antagonistas & inibidores , Imidazóis/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridazinas/uso terapêutico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Gerenciamento Clínico , Feminino , Proteínas de Fusão bcr-abl/genética , Humanos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Piridazinas/administração & dosagem , Piridazinas/efeitos adversos , Estudos Retrospectivos , Resultado do TratamentoAssuntos
Linfoma Folicular/diagnóstico , Linfoma de Efusão Primária/diagnóstico , Idoso de 80 Anos ou mais , Feminino , Infecções por HIV/complicações , Infecções por Herpesviridae/complicações , Herpesvirus Humano 8/isolamento & purificação , Humanos , Linfoma Folicular/virologia , Linfoma de Efusão Primária/virologiaAssuntos
Adenina/análogos & derivados , Tamponamento Cardíaco/diagnóstico , Tamponamento Cardíaco/etiologia , Leucemia Linfocítica Crônica de Células B/complicações , Piperidinas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Adenina/efeitos adversos , Adenina/uso terapêutico , Idoso , Biomarcadores , Biópsia , Ecocardiografia , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Radiografia Torácica , Avaliação de SintomasRESUMO
Membranous nephropathy (MN) is a common glomerular disease that is characterized by diffuse thickening of the glomerular basement membrane, and a common cause of nephrotic syndrome (NS). MN is often accompanied with malignant disease; The solid tumors are commonly associated with MN, whereas hematological malignancies are rarely found in patients with MN. A 68-year-old man with a history of diabetes mellitus visited a hospital with a chief complaint of general fatigue. He was previously not diagnosed with any complications of diabetes. Computed tomography revealed a pancreatic tumor, and the pathological findings of the biopsied tumor revealed the tumor was diffuse large B-cell lymphoma (DLBCL). Concurrently, he developed severe proteinuria, hypoalbuminemia, systemic edema and hyperlipidemia, consistent with the diagnosis of NS. The biopsied renal specimen revealed minute spike lesions of glomerular basement membrane, and abnormal lymphocytes infiltrated in the kidney interstitially. Anti-glomerular basement membrane antibody, proteinase-3-/myeloperoxidase antineutrophil cytoplasmic antibody and hepatitis B antigenemia, are absent in the patient. Serum anti-phospholipase A2 receptor (PLA2R) antibody (marker for primary MN) was not detected. A diagnosis of secondary MN induced by DLBCL was made. He received rituximab containing chemotherapy for DLBCL, resulting in amelioration of both DLBCL and MN. We report the rare case of a patient co-existing NS and DLBCL. DLBCL might be pathogenesis of NS; the findings are supported by the presence of MN, an underlying malignancy (DLBCL), and the lack of anti-PLA2R antibodies. Although further investigation is warranted, our case suggests that DLBCL is a possible cause of secondary MN.
Assuntos
Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Síndrome Nefrótica/diagnóstico por imagem , Idoso , Membrana Basal/patologia , Terapia Combinada , Complicações do Diabetes , Humanos , Imunoterapia , Inflamação , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/terapia , Masculino , Síndrome Nefrótica/complicações , Síndrome Nefrótica/patologia , Síndrome Nefrótica/terapia , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Receptores da Fosfolipase A2/imunologia , Rituximab/farmacologia , Tomografia Computadorizada por Raios XAssuntos
Cromossomos Humanos Par 11/ultraestrutura , Cromossomos Humanos Par 14/ultraestrutura , Imunossupressores/efeitos adversos , Linfoma Difuso de Grandes Células B/induzido quimicamente , Metotrexato/efeitos adversos , Proteínas de Neoplasias/análise , Neprilisina/análise , Proteínas de Fusão Oncogênica/análise , Proteínas Proto-Oncogênicas c-bcl-6/análise , Translocação Genética , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 14/genética , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Humanos , Imunossupressores/uso terapêutico , Linfonodos/patologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Metotrexato/uso terapêutico , Proteínas de Neoplasias/genética , Proteínas de Fusão Oncogênica/genética , Prednisolona/administração & dosagem , Indução de Remissão , Rituximab/administração & dosagem , Vincristina/administração & dosagemRESUMO
Graft-versus-host disease (GVHD) is a potentially life-threatening complication of allogeneic stem cell transplantation (Allo-SCT). Chronic GVHD, which typically presents more than 100 days after Allo-SCT, can resemble manifestations of autoimmune disease; however, there are only a few reports on the development of Crohn's disease (CD) after Allo-SCT. Here, we report a case of steroid-refractory CD after umbilical cord blood transplantation (CBT), which was dramatically improved with administration of anti-tumor necrosis factor-alpha (anti-TNF-alpha) antibodies. A 21-year-old woman with refractory Hodgkin lymphoma underwent CBT and achieved complete remission. About 1 year after CBT, she complained of intermittent abdominal pain and bloody diarrhea, and colonoscopy revealed multiple longitudinal colonic ulcers with a cobblestone appearance; thus, based on the colonoscopy findings, she was diagnosed with CD. We considered a CD-like manifestation of gastrointestinal GVHD and initially administered steroids, but the therapeutic effect was poor. Then, we administered anti-TNF-alpha antibodies, infliximab, and then adalimumab, which resulted in rapid improvement of abdominal symptoms, with no recurrence despite discontinuation of this therapy. Anti-TNF-alpha antibodies are effective for CD after Allo-SCT, which can be considered as a subsequent complication of GVHD.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Doença de Crohn/etiologia , Doença de Crohn/terapia , Doença de Hodgkin/terapia , Adalimumab/administração & dosagem , Terapia Combinada , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/terapia , Humanos , Imunoterapia/métodos , Infliximab/administração & dosagem , Indução de Remissão , Transplante Homólogo/efeitos adversos , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologia , Adulto JovemRESUMO
Patients with myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) are often asymptomatic and thus can remain undiagnosed until they become symptomatic due to progression to the accelerated phase (AP) or transformation to acute leukemia (leukemic transformation; LT). We herein report the case of a previously healthy 38-year-old man who had hyperleukocytosis with dysplastic myeloid precursor cells and severe disseminated intravascular coagulation. Hematopoietic recovery with features of atypical chronic myeloid leukemia (aCML) after induction chemotherapy was a diagnostic clue. Although rare, this case highlights the limitation of the diagnostic approach for aCML with AP or LT at the initial presentation.
Assuntos
Coagulação Intravascular Disseminada/complicações , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/complicações , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/patologia , Adulto , Antineoplásicos/uso terapêutico , Humanos , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/tratamento farmacológico , Leucocitose/complicações , MasculinoRESUMO
Patients with FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) acute myeloid leukemia (AML) respond to conventional induction chemotherapy, with remission rates similar to those seen in other subtypes; however, they are much more likely to relapse and relapse is rapid. For this reason, eligible patients receive consolidation therapy with early allogenic transplantation, but the recurrence rate remains high, even after transplantation. Moreover, the optimal therapy for patients with FLT3-ITD AML who relapse after allogeneic hematopoietic stem cell transplantation remains unclear. Here, we report a case in which graft-versus-leukemia (GVL) effects were induced by gilteritinib administration after a second transplant from the same donor, resulting in sustained remission of early FLT3-ITD AML relapse after allogeneic transplantation. Several studies suggest that the benefits of FLT3 tyrosine kinase inhibitors (FLT3-TKI) after allogeneic transplantation are attributable to GVL induction, as well as direct effects on FLT3 mutation-positive leukemia cells. With this in mind, we induced lymphodepletion using L-PAM to further enhance GVL induction by donor lymphocytes and FLT3-TKI. We believe that enhancement of GVL induction by lymphodepletion should be considered before FLT3-TKI use, if the prognosis is very poor, such as in patients with recurrence following allogeneic transplantation.
Assuntos
Compostos de Anilina/administração & dosagem , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/cirurgia , Pirazinas/administração & dosagem , Recidiva , Sequências de Repetição em Tandem/genética , Doadores de Tecidos , Tirosina Quinase 3 Semelhante a fms/genética , Compostos de Anilina/farmacologia , Feminino , Efeito Enxerto vs Leucemia/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/imunologia , Mutação , Pirazinas/farmacologia , Indução de Remissão , Reoperação , Resultado do Tratamento , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidoresAssuntos
Injúria Renal Aguda/sangue , Injúria Renal Aguda/diagnóstico , DNA Nucleotidilexotransferase/sangue , Leucemia-Linfoma Linfoblástico de Células T Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Injúria Renal Aguda/terapia , Evolução Fatal , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Adulto JovemAssuntos
Cromossomos Humanos Par 19/genética , Cromossomos Humanos Par 22/genética , Infecções por Vírus Epstein-Barr/genética , Translocação Genética , Cariótipo Anormal , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfócitos B/química , Linfócitos B/virologia , Cromossomos Humanos Par 19/ultraestrutura , Cromossomos Humanos Par 22/ultraestrutura , Cisplatino/administração & dosagem , Ciclofosfamida/administração & dosagem , Citarabina/administração & dosagem , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Humanos , Linfoma Difuso de Grandes Células B/virologia , Masculino , Metilprednisolona/administração & dosagem , Prednisona/administração & dosagem , RNA Neoplásico/análise , RNA Viral/análise , Rituximab/administração & dosagem , Vincristina/administração & dosagemRESUMO
Although the prognosis of chronic myeloid leukemia (CML) in blastic crisis remains poor, some patients achieve long-term remission after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This may be attributable to graft-versus-leukemia (GVL) effects by donor lymphocytes, but their regulating mechanisms are unclear. Antitumor natural killer (NK) cell immunity is assumed to be important in CML, and we have previously shown that allelic polymorphisms of killer immunoglobulin-like receptors (KIRs) and histocompatibility leukocyte antigens (HLAs) are associated with the response of CML to tyrosine kinase inhibitors. Here, we report a case of CML in blastic phase who received HLA-matched but KIR3DL1 allelic-mismatched allo-HSCT. After transplant, decreased BCR-ABL transcript levels and enhanced NK cell activity were transiently observed. However, reconstitution of KIR3DL1-expressing NK cells occurred, which was associated with diminished NK cell activity and increased BCR-ABL. This case indicates the potential significance of KIR3DL1 in NK cell-mediated GVL activity following allo-HSCT. To the best of our knowledge, this is the first report to analyze the association between sequential KIR3DL1 expression and activity of NK cells after allo-HSCT. Selecting donors with KIR3DL1-null alleles may maintain competent GVL effects and provide improved outcomes in allo-HSCT for CML.