RESUMO
Adenosine-to-inosine RNA editing, which is catalyzed by adenosine deaminases acting on RNA (ADAR) family of enzymes, ADAR1 and ADAR2, has been shown to contribute to multiple cancers. However, other than the chronic myeloid leukemia blast crisis, relatively little is known about its role in other types of hematological malignancies. Here, we found that ADAR2, but not ADAR1 and ADAR3, was specifically downregulated in the core-binding factor (CBF) acute myeloid leukemia (AML) with t(8;21) or inv(16) translocations. In t(8;21) AML, RUNX1-driven transcription of ADAR2 was repressed by the RUNX1-ETO additional exon 9a fusion protein in a dominant-negative manner. Further functional studies confirmed that ADAR2 could suppress leukemogenesis specifically in t(8;21) and inv16 AML cells dependent on its RNA editing capability. Expression of 2 exemplary ADAR2-regulated RNA editing targets coatomer subunit α and component of oligomeric Golgi complex 3 inhibits the clonogenic growth of human t(8;21) AML cells. Our findings support a hitherto, unappreciated mechanism leading to ADAR2 dysregulation in CBF AML and highlight the functional relevance of loss of ADAR2-mediated RNA editing to CBF AML.
Assuntos
Fatores de Ligação ao Core , Leucemia Mieloide Aguda , Humanos , Regulação para Baixo , Fatores de Ligação ao Core/metabolismo , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Edição de RNA , Adenosina Desaminase/genética , Adenosina Desaminase/metabolismo , Leucemia Mieloide Aguda/genética , Adenosina/metabolismoRESUMO
OBJECTIVES: CCAAT/enhancer-binding protein α (CEBPA) is an essential transcription factor for myeloid differentiation. Not only mutation of the CEBPA gene, but also promoter methylation, which results in silencing of CEBPA, contributes to the pathogenesis of acute myeloid leukemia (AML). We sought for another differentially methylated region (DMR) that associates with the CEBPA silencing and disease phenotype. METHODS: Using databases, we identified a conserved DMR in the CEBPA 3'-untranslated region (UTR). RESULTS: Methylation-specific PCR analysis of 231 AML cases showed that hypermethylation of the 3'-UTR was associated with AML that had a myeloid/NK/T-cell phenotype and downregulated CEBPA. Most of these cases were of an immature phenotype with CD7/CD56 positivity. These cases were significantly associated with lower hemoglobin levels than the others. Furthermore, we discovered that the CEBPA 3'-UTR DMR can enhance transcription from the CEBPA native promoter. In vitro experiments identified IKZF1-binding sites in the 3'-UTR that are responsible for this increased transcription of CEBPA. CONCLUSIONS: These results indicate that the CEBPA 3'-UTR DMR is a novel regulatory element of CEBPA related to myeloid/NK/T-cell lineage leukemogenesis. Transcriptional regulation of CEBPA by IKZF1 may provide a clue for understanding the fate determination of myeloid vs. NK/T-lymphoid progenitors.
Assuntos
Regiões 3' não Traduzidas , Proteínas Estimuladoras de Ligação a CCAAT/genética , Predisposição Genética para Doença , Leucemia Aguda Bifenotípica/diagnóstico , Leucemia Aguda Bifenotípica/genética , Sequências Reguladoras de Ácido Nucleico , Sítios de Ligação , Biomarcadores , Metilação de DNA , Epigênese Genética , Estudos de Associação Genética , Humanos , Imunofenotipagem , Leucemia Aguda Bifenotípica/metabolismo , Células Mieloides/metabolismo , Células Mieloides/patologia , Células T Matadoras Naturais/metabolismo , Células T Matadoras Naturais/patologia , Fenótipo , Ligação ProteicaRESUMO
We examined the incidence and prognostic effect of IDH1 and IDH2 mutations in 233 Japanese adults with acute myeloid leukemia (AML). IDH1 R132 mutations were detected in 20 (8.6%) patients with AML. IDH2 mutations were found in 19 (8.2%, 17 R140 and two R172) patients. IDH1 and IDH2 mutations were mutually exclusive and were associated with normal karyotype AML, cytogenetic intermediate-risk group, and NPM1 mutations. Five-year overall survival (OS) rates were significantly lower (15.6%) in patients harboring the IDH mutations than in patients lacking the IDH mutation (32.0%) in the entire cohort of AML (P = 0.005). Among patients aged 59 yr or younger with IDH mutations, 5-yr OS in patients who underwent allogeneic stem cell transplantation (SCT) was significantly higher than that in those not receiving allogeneic SCT (50% vs. 10.6%, P = 0.020). Of 51 patients with NPM1 mutations, there was no significant difference in 5-yr OS rates between patients with and those without the IDH mutations. In contrast, among 175 patients lacking the NPM1 mutations, 5-yr OS rate in patients with IDH mutations was significantly lower than that in those without IDH mutations (0% vs. 34.7%, P = <0.001). These data suggest that IDH mutations have an unfavorable effect in AML, especially AML with the NPM1 wild type and younger AML patients with IDH mutations may benefit from allogeneic SCT.
Assuntos
Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/genética , Mutação , Proteínas Nucleares/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Feminino , Frequência do Gene , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Nucleofosmina , Avaliação de Resultados da Assistência ao Paciente , Prognóstico , Adulto JovemRESUMO
This study investigated changes in treatment modalities and outcomes of chronic myeloid leukemia in the chronic phase (CP-CML) after the approval of second-generation tyrosine kinase inhibitors (2G-TKIs) for first-line therapy. Patients were grouped into those who underwent TKI therapy up to December 2010 (imatinib era group, n = 185) and after January 2011 (2G-TKI era group, n = 425). All patients in the imatinib era group were initially treated with imatinib, whereas patients in the 2G-TKI era group were mostly treated with dasatinib (55%) or nilotinib (36%). However, outcomes including progression-free survival, overall survival, and CML-related death (CRD) did not differ significantly between groups. When stratified by risk scores, the prognostic performance of the ELTS score was superior to that of the Sokal score. Even though both scoring systems predicted CRD in the imatinib era, only the ELTS score predicted CRD in the 2G-TKI era. Notably, the outcome of patients classified as high-risk by ELTS score was more favorable in the 2G-TKI era group than in the imatinib era group. Thus, expanding treatment options may have improved patient outcomes in CP-CML, particularly in patients classified as high-risk by ELTS score.
Assuntos
Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva , Inibidores de Proteínas Quinases , Humanos , Inibidores de Proteínas Quinases/uso terapêutico , Estudos Retrospectivos , Masculino , Pessoa de Meia-Idade , Feminino , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Idoso , Adulto , Mesilato de Imatinib/uso terapêutico , Resultado do Tratamento , Dasatinibe/uso terapêutico , Idoso de 80 Anos ou mais , Pirimidinas/uso terapêutico , Adolescente , Adulto Jovem , PrognósticoRESUMO
Alterations in the IKZF1 gene are associated with poor prognosis in pediatric B-cell acute lymphoblastic leukemia (B-ALL). We examined the relationship between IKZF1 alterations and clinical findings in 78 adult patients with B-ALL. Aberrant isoforms of IKZF1 were detected using RT-PCR. The copy numbers of IKZF1 exons and fusion genes caused by exon deletions were determined using RQ-PCR and genomic PCR, respectively. We detected aberrant IKZF1 isoforms in 20 of the 78 patients (13 Ik6 and seven Ik10) and deletions of the entire or parts of the IKZF1 gene in 40 of 70 patients. No IKZF1 point mutations were detected by direct sequencing. Nineteen Ik6 and Ik10 isoforms had been generated through genomic exon deletions, but one through aberrant splicing. In total, 41 of the 78 (52.6%) patients harbored IKZF1 alterations, which were identified in 20 of 24 (83.3%) patients with Philadelphia chromosome (Ph)-positive B-ALL compared with 21 of 54 (38.9%) Ph-negative B-ALL (P = 0.0004). IKZF1 alterations are highly involved even in adults with B-ALL. To fully detect IKZF1 alterations, several methods with alternative approaches are required. To elucidate the clinical significance of IKZF1 alterations in adult B-ALL, our study warrants prospective clinical studies with a full analysis of IKZF1 alterations.
Assuntos
Fator de Transcrição Ikaros/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Sequência de Bases , Aberrações Cromossômicas , Variações do Número de Cópias de DNA , Feminino , Genes Dominantes , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Isoformas de RNA , Adulto JovemRESUMO
ABL1-tyrosine kinase inhibitors (TKIs) are an established treatment choice for patients with chronic myeloid leukemia in the chronic phase (CML-CP). However, effects of TKI dose modification have not been well investigated. In this study, we retrospectively analyzed 178 patients with newly diagnosed CML-CP who were treated with dasatinib or nilotinib, focusing on age and dose effects. Efficacy as measured by cumulative major molecular response (MMR) and molecular response 4.5 rates did not differ significantly between the younger group and elderly group. Elderly patients who started nilotinib at a reduced dose had similar or better efficacy outcomes (including cumulative MMR and continuation ratios) than other groups, and elderly patients who started dasatinib at a reduced dose had the lowest MMR ratio and longest MMR duration. Effects of dose modification based on age and TKI selection can be attributed to flexible management of TKI therapy in real-world practice, but further studies are required to validate the findings of this study.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Idoso , Dasatinibe/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Estudos Retrospectivos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Pirimidinas , Resultado do TratamentoRESUMO
Objective Pleural effusion (PE) is a common adverse event that occurs during dasatinib therapy for chronic myeloid leukemia (CML). However, the pathomechanism of PE and appropriate management of Asian patients with CML have not been elucidated. This study investigated the incidence rate, risk, and appropriate management of PE in Asian patients with CML treated with dasatinib. Methods We retrospectively collected data on patients in the chronic phase of CML who received first-line dasatinib therapy and were registered in the CML-Cooperative Study Group database. Patients We identified 44 cases of PE in a series of 89 patients and analyzed previously reported risk factors and effective management of PE. Results A univariate analysis revealed that age, diabetes mellitus, chronic renal failure, hypertension, the history of cardiovascular events, and dasatinib dose were significantly associated with PE. A multivariate analysis revealed that age ≥65 years old was the only independent risk factor for PE. Dasatinib dose reduction and switching to a tyrosine kinase inhibitor showed a statistically significant difference in effectively reducing PE volume compared to single diuretic use. Conclusion Although further studies are warranted, our observations showed that advanced age is a significant risk factor for PE, and tyrosine kinase inhibitor dose reduction or replacement of dasatinib may be an effective management strategy for PE in Asian CML patients who received first-line treatment with dasatinib in real-world clinical practice.
Assuntos
Dasatinibe , Leucemia Mielogênica Crônica BCR-ABL Positiva , Derrame Pleural , Idoso , Humanos , Dasatinibe/efeitos adversos , População do Leste Asiático , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Derrame Pleural/induzido quimicamente , Derrame Pleural/epidemiologia , Derrame Pleural/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Estudos Retrospectivos , Fatores de RiscoRESUMO
INTRODUCTION: Few studies have reported the outcomes of adolescents and young adults (AYAs) with chronic-phase chronic myeloid leukaemia (CML-CP) on tyrosine kinase inhibitors (TKIs). MATERIALS AND METHODS: We retrospectively analysed the clinical features, treatment response, and long-term outcomes of 42 AYA patients, in comparison to older patients. The initial therapies of AYA patients between 2001 and 2016 included imatinib (n = 24), dasatinib (n = 13) and nilotinib (n = 5). RESULTS: In AYA patients, the peripheral blood (PB) white blood cell count and percentage of blasts at the diagnosis were significantly higher, haemoglobin levels were lower and the spleen size was larger. The major molecular response (MMR), event-free survival (EFS) and overall survival (OS) rates were comparable. A sub-analysis comparing imatinib to second-generation TKIs as the initial therapy also showed that their prognosis was comparable. DISCUSSION: In conclusion, the tumour burden at the diagnosis of CML-CP is higher in AYA patients; however, their prognosis was not worse in comparison to older patients treated with TKIs. KEY MESSAGESFew studies have reported the outcomes of adolescents and young adults (AYAs) with chronic-phase chronic myeloid leukaemia (CML-CP) on tyrosine kinase inhibitors (TKIs). This study showed the tumour burden at the diagnosis of CML-CP is higher in AYA pa tients; however, their prognosis was not worse in comparison to older patients treated with TKIs. Understanding the biological and non-biological features of AYA patients with CML-CP on TKI therapy is essential for better management and to improve the outcomes.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Leucemia Mieloide de Fase Crônica , Adolescente , Humanos , Mesilato de Imatinib/efeitos adversos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mieloide de Fase Crônica/diagnóstico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Estudos Retrospectivos , Adulto JovemRESUMO
C/EBPalpha plays an essential role as a transcription factor in myeloid cell differentiation. Here, we describe a Japanese family in which two individuals with acute myeloid leukemia (AML) and one healthy individual had an identical 4-base pair insertion in the N-terminal region of CEBPA (350_351insCTAC), resulting in the termination at codon 107 (I68fsX107). The father and a son at diagnosis of AML had different in-frame insertion mutations in the C-terminal region of C/EBPalpha. These C-terminal mutations disappeared upon remission in both patients. Interestingly, the father showed different in-frame insertion mutations in the C-terminal CEBPA at the time of diagnosis and relapse. These data strongly suggest that the N-terminal C/EBPalpha mutation predisposes to the occurrence of a C-terminal C/EBPalpha mutation as a secondary genetic hit, causing AML.
Assuntos
Proteína alfa Estimuladora de Ligação a CCAAT/genética , Leucemia Mieloide Aguda/genética , Mutação , Adolescente , Adulto , Criança , Pré-Escolar , Primers do DNA , DNA de Neoplasias/genética , Feminino , Mutação em Linhagem Germinativa , Humanos , Masculino , Pessoa de Meia-Idade , Mutagênese Insercional , Linhagem , Reação em Cadeia da Polimerase , Deleção de SequênciaRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMO
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive subtype of acute leukemia, the cell of origin of which is considered to be precursors of plasmacytoid dendritic cells (pDCs). Since translocation (6;8)(p21;q24) is a recurrent anomaly for BPDCN, we demonstrate that a pDC-specific super-enhancer of RUNX2 is associated with the MYC promoter due to t(6;8). RUNX2 ensures the expression of pDC-signature genes in leukemic cells, but also confers survival and proliferative properties in BPDCN cells. Furthermore, the pDC-specific RUNX2 super-enhancer is hijacked to activate MYC in addition to RUNX2 expression, thereby promoting the proliferation of BPDCN. We also demonstrate that the transduction of MYC and RUNX2 is sufficient to initiate the transformation of BPDCN in mice lacking Tet2 and Tp53, providing a model that accurately recapitulates the aggressive human disease and gives an insight into the molecular mechanisms underlying the pathogenesis of BPDCN.
Assuntos
Subunidade alfa 1 de Fator de Ligação ao Core/genética , Células Dendríticas/patologia , Leucemia Mieloide Aguda/genética , Proteínas Proto-Oncogênicas c-myc/genética , Animais , Proliferação de Células/genética , Cromossomos Humanos Par 6/genética , Cromossomos Humanos Par 8/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Proteínas de Ligação a DNA/genética , Dioxigenases , Elementos Facilitadores Genéticos/genética , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas , Humanos , Células Jurkat , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Translocação Genética/genética , Irradiação Corporal TotalRESUMO
We performed a retrospective study to evaluate the incidence of second malignancies (SMs) in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs). We analyzed data from 339 patients with CML who were extracted from the CML Cooperative Study Group database. The standardized incidence ratio (SIR) was calculated to assess the risk of SMs using data from the Cancer Registries in Japan. The median follow-up was 65 months. SMs developed in 14 patients (4.1%, 10 men, 4 women) after the start of TKIs. The median age was 69 years at the time of the CML diagnosis and 72.5 years at the time of the SM diagnosis. Ten patients were treated with imatinib, three with dasatinib, and one with nilotinib as the initial treatment. The SIR for all malignancies was 1.05 (95% CI 0.50-1.93) for men and 1.08 (95% CI 0.29-2.76) for women. The difference in the overall survival (OS) of patients with or without SMs was not statistically significant (5-year OS: 82.5% vs. 92.9%; p = 0.343). A subgroup analysis of 166 patients treated with second-generation TKIs (92 dasatinib, 74 nilotinib) showed that the SIRs for all malignancies were 1.33 (95% CI 0.36-3.41) for men and 0 for women. In conclusion, the incidence of SMs in CML patients during TKI treatment was the same as that in the general Japanese population. There was no evidence of an increase in the incidence of SMs during second-generation TKI treatment. Furthermore, the occurrence of SMs during TKI treatment did not affect the survival or mortality in our cohort.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Segunda Neoplasia Primária/etiologia , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Incidência , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/epidemiologia , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Análise de SobrevidaAssuntos
Subunidade alfa 2 de Fator de Ligação ao Core/fisiologia , Proteínas de Ligação a DNA/genética , Leucemia Mieloide/patologia , Proteínas de Fusão Oncogênica , Proteínas Proto-Oncogênicas/genética , Proteína 1 Parceira de Translocação de RUNX1/fisiologia , Fatores de Transcrição/genética , Fatores Etários , Animais , Leucemia Mieloide/genética , Leucemia Mieloide/metabolismo , Camundongos , Camundongos Knockout , Translocação GenéticaAssuntos
Leucemia Promielocítica Aguda/tratamento farmacológico , Segunda Neoplasia Primária/tratamento farmacológico , Proteínas de Fusão Oncogênica/genética , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagem , Benzamidas , Humanos , Mesilato de Imatinib , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/genética , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/diagnóstico , Indução de Remissão/métodosAssuntos
Janus Quinase 2/genética , Leucemia Mieloide/genética , Proteínas Proto-Oncogênicas c-kit/genética , Translocação Genética , Tirosina Quinase 3 Semelhante a fms/genética , Doença Aguda , Adulto , Idoso , Substituição de Aminoácidos , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 8/genética , Feminino , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide/patologia , Masculino , MutaçãoAssuntos
Cromossomos Humanos Par 17/genética , Leucemia Promielocítica Aguda/genética , Proteínas de Fusão Oncogênica/análise , Proteínas de Fusão Oncogênica/genética , Fator de Transcrição STAT5/análise , Fator de Transcrição STAT5/genética , Transcrição Gênica/genética , Adulto , Idoso , Sequência de Aminoácidos , Sequência de Bases , Humanos , Cariotipagem , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Proteínas de Fusão Oncogênica/química , Fator de Transcrição STAT5/químicaRESUMO
TIS11D is an AU-rich element binding protein that is involved in RNA metabolism and definitive hematopoiesis. Although disruption of genes related to hematopoiesis often leads to the development of leukemia and lymphoma, the involvement of TIS11D in hematological malignancies remains to be determined. In the present study, we identified a heterozygous frameshift mutation (I373fsX91) in the carboxy-terminus of the TIS11D gene in leukemic cells from a patient with acute myeloid leukemia. Moreover, biallelic inactivation of the TIS11D gene resulting from a hemizygous frameshift mutation (G107fsX80) was identified in the Burkitt's lymphoma cell line DG75. In HeLa cells, overexpression of wild-type TIS11D protein (TIS11D(WT)) induced growth inhibition and an S phase checkpoint response, while the mutant protein (TIS11D(I373fsX91)) showed a diminished effect. Interestingly, this response was accompanied by p21 downregulation, which is frequently seen in the cellular response to ultraviolet irradiation. These data suggest that the dysregulation of TIS11D function is associated with the pathogenesis of certain types of leukemia.
Assuntos
Mutação da Fase de Leitura , Leucemia Mieloide Aguda/genética , Fatores de Transcrição/genética , Animais , Linfoma de Burkitt/genética , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Genes p53 , Células HeLa , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Camundongos , Camundongos Knockout , Proteínas de Ligação a RNA/genética , Análise de Sequência de DNARESUMO
The echinocandins provide an attractive new option for prophylactic and empirical treatment of invasive fungal infections in patients with neutropenia after intensive cytotoxic chemotherapy or hematopoietic stem cell transplantation. We present two patients with hematological diseases who experienced massive intravascular hemolysis followed by renal failure after administration of micafungin. In indirect antiglobulin test, significant agglutination was observed when red blood cells were exposed to the mixture of micafungin and either of the patients' plasma samples, indicating that production of antibodies directed against both micafungin and red blood cell membrane induced hemolysis attack. Micafungin-mediated immune hemolysis represents an uncommon but life-threatening adverse reaction leading to renal failure.