RESUMO
Acute promyelocytic leukemia (APL) with typically PML::RARA fusion gene caused by t (15;17) (q22; q12) was distinguished from other types of acute myeloid leukemia. In a subset of patients with APL, t (15;17) (q22;q21) and PML::RARA fusion cannot be detected. In this report, we identified the coexistence of STAT3::RARA and RARA::STAT5b fusions for the first time in a variant APL patient lacking t (15;17)(q22;q21)/PML::RARA fusion. Then, this patient was resistant to all-trans retinoic acid combined arsenic trioxide chemotherapy. Accurate detection of RARA gene partners is crucial for variant APL, and effective therapeutic regime is urgently needed.
Assuntos
Leucemia Promielocítica Aguda , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/genética , Tretinoína , Fator de Transcrição STAT3/genéticaRESUMO
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm defined by the presence of t(9;22)(q34;q11.2)/BCR::ABL1. Additional chromosomal abnormalities play an important role in the progression to CML. However, the additional fusion gene was rarely reported such as CBFB::MYH11. In this report, we described two cases of the co-occurrence of BCR::ABL1 and SET::NUP214 in CML-BP for the first time, which is associated with poor outcomes during tyrosine kinase inhibitor (TKI) treatment. Meanwhile, we retrospectively analyzed SET::NUP214 fusion transcript of the two cases at initial diagnosis of the CML chronic phase by quantitative RT-PCR, and detected at a ratio of 1.63% and 1.50%, respectively. SET::NUP214 may promote disease progression during the transformation of CML. This study highlights the importance of extended molecular testing at the initial diagnosis of CML-CP at TKI resistance and/or disease transformation.
Assuntos
Crise Blástica , Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Crise Blástica/genética , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Complexo de Proteínas Formadoras de Poros Nucleares , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Estudos RetrospectivosRESUMO
Atypical chronic myeloid leukemia (CML) is a rare BCR::ABL1-negative hematopoietic stem cell disease characterized by granulocytic proliferation and granulocytic dysplasia. Due to both the challenging diagnosis and the rarity of atypical CML, comprehensive molecular annotation-based analyses of this disease population have been scarce, and it is currently difficult to identify the optimal treatment for atypical CML. To explore atypical CML genomic landscape and treatment options, we performed a systematic retrospective of the clinical data and outcomes of 31 atypical CML patients. We observed that the molecular landscape of atypical CML was highly heterogeneous, with multiple molecular events driving its pathogenesis. Patients with atypical CML had a low response to current therapies, with an overall response rate (ORR) of 33.3% to hypomethylating agent (HMA)-based therapy. The current treatment strategies, including hematopoietic stem cell transplantation (HSCT), did not improve overall survival (OS) in atypical CML patients, with a median survival of 20 months. Thus, the benefits from HSCT and candidates for HSCT remain to be further evaluated. Acute myeloid leukemia (AML)-like chemotherapy followed by bridging allogeneic HSCT may be an ideal regimen for suitable individuals. The large-scale and prospective clinical studies will help to address the dilemma.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa , Humanos , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/terapia , Estudos Retrospectivos , Estudos Prospectivos , Organização Mundial da Saúde , Biologia MolecularRESUMO
Mixed phenotype acute leukemia (MPAL) is a subtype of leukemia in which lymphoid and myeloid markers are co-expressed. Knowledge regarding the genetic features of MPAL is lacking due to its rarity and heterogeneity. Here, we applied an integrated genomic and transcriptomic approach to explore the molecular characteristics of 176 adult patients with MPAL, including 86 patients with T-lymphoid/myeloid MPAL (T/My MPAL-NOS), 42 with Ph+ MPAL, 36 with B-lymphoid/myeloid MPAL (B/My MPAL-NOS), 4 with t(v;11q23), and 8 with MPAL, NOS, rare types. Genetically, T/My MPAL-NOS was similar to B/T MPAL-NOS but differed from Ph+ MPAL and B/My MPAL-NOS. T/My MPAL-NOS exhibited higher CEBPA, DNMT3A, and NOTCH1 mutations. Ph+ MPAL demonstrated higher RUNX1 mutations. B/T MPAL-NOS showed higher NOTCH1 mutations. By integrating next-generation sequencing and RNA sequencing data of 89 MPAL patients, we defined eight molecular subgroups (G1-G8) with distinct mutational and gene expression characteristics. G1 was associated with CEBPA mutations, G2 and G3 with NOTCH1 mutations, G4 with BCL11B rearrangement and FLT3 mutations, G5 and G8 with BCR::ABL1 fusion, G6 with KMT2A rearrangement/KMT2A rearrangement-like features, and G7 with ZNF384 rearrangement/ZNF384 rearrangement-like characteristics. Subsequently, we analyzed single-cell RNA sequencing data from five patients. Groups G1, G2, G3, and G4 exhibited overexpression of hematopoietic stem cell disease-like and common myeloid progenitor disease-like signatures, G5 and G6 had high expression of granulocyte-monocyte progenitor disease-like and monocyte disease-like signatures, and G7 and G8 had common lymphoid progenitor disease-like signatures. Collectively, our findings indicate that integrative genomic and transcriptomic profiling may facilitate more precise diagnosis and develop better treatment options for MPAL.
Assuntos
Leucemia Mieloide Aguda , Transcriptoma , Humanos , Doença Aguda , Fenótipo , GenômicaRESUMO
Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML), which is characterized by the reciprocal t (15;17) (q24; q21) translocation, resulting in PML-RARA gene fusion. Therapy-related AML (t-AML) is a serious complication after cytotoxic and/or radiation therapy in many malignant diseases. In this report, MLL/KMT2A-MON2, with balanced chromosomal translocation t (11;12) (q23; q14), was identified as a novel fusion in a child transformed to t-AML after successful treatment of APL. This study emphasized that clinical monitoring with an integrated laboratory approach is essential for the diagnosis and treatment of t-AML.
Assuntos
Antineoplásicos/efeitos adversos , Histona-Lisina N-Metiltransferase/genética , Leucemia Mieloide Aguda/genética , Leucemia Promielocítica Aguda/tratamento farmacológico , Proteína de Leucina Linfoide-Mieloide/genética , ATPases Translocadoras de Prótons/genética , Antineoplásicos/uso terapêutico , Pré-Escolar , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 12/genética , Humanos , Leucemia Mieloide Aguda/induzido quimicamente , Leucemia Promielocítica Aguda/genética , Masculino , Proteínas de Fusão Oncogênica/genética , Translocação Genética , Sequenciamento Completo do GenomaAssuntos
Azacitidina , Leucemia Mieloide Aguda , Sulfonamidas , Adulto , Humanos , Decitabina/uso terapêutico , Azacitidina/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/diagnóstico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
The diagnostic hallmark of acute promyelocytic leukemia (APL) is the reciprocal translocation t(15;17), resulting in the characteristic PML-RARA fusion; however, patients occasionally have masked PML-RARArearrangements. We report an APL case with no evidence of t(15;17) or PML-RARA rearrangement by karyotype or commercial reverse transcription polymerase chain reaction analyses. Fluorescence in situ hybridization detected a small RARA insertion signal within PML. mRNA sequencing identified a novel PML-RARA transcript generated from the juxtaposition of PMLIIa (exons 1-4, 6, and 7ab) and RARA exons (3-9), with novel breakpoints in PML exon 7b and RARA exon 3. The patient achieved molecular remission after the second consolidation chemotherapy and remains in complete remission 22 months after initial presentation. This is the first report of an APL case presenting with submicroscopic ins(15;17) and simultaneous novel breakpoints in both PML and RARA. This case highlights the importance of sequence analysis to confirm APL diagnosis and for subsequent monitoring of minimal residual disease.
Assuntos
Éxons , Loci Gênicos , Leucemia Promielocítica Aguda/genética , Mutagênese Insercional , Proteínas de Fusão Oncogênica/genética , Adulto , Humanos , Hibridização in Situ Fluorescente , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/patologia , MasculinoRESUMO
We retrospectively evaluated the efficacy and safety of dasatinib among 48 Chinese patients with chronic phase chronic myeloid leukaemia. The proportions of patients achieving the optimal molecular responses at 3, 6, and 12 months, a major molecular response (MMR) rate and a complete cytogenetic response (CCyR) rate were 87.0, 87.0, 72.2, 45.8, and 72.7% for patients with dasatinib as second-line therapy, and 34.8, 34.8, 33.3, 20.8, and 46.2% as third-line therapy, respectively. A BCR-ABL1 transcript level on the International Scale (BCR-ABL1IS) of ≤10% at the initiation of -dasatinib treatment was found to be associated with a higher probability of achieving MMR. Among patients with a -BCR-ABL1IS higher than 10% at initiation of dasatinib treatment, dasatinib showed better performance as a second-line therapy than as a third-line therapy. The patients who achieved an optimal molecular response at 3 months had a superior cumulative incidence of MMR and CCyR compared with patients who failed to achieve such a response. Dasatinib induced considerable responses as a second-line treatment, especially in patients with a BCR-ABL1IS ≤10% at initiation of treatment, whereas the efficacy was limited in patients receiving third-line therapy with a BCR-ABL1IS >10% at the initiation of treatment.
Assuntos
Aberrações Cromossômicas , Dasatinibe/administração & dosagem , Proteínas de Fusão bcr-abl , Leucemia Mielogênica Crônica BCR-ABL Positiva , Inibidores de Proteínas Quinases/administração & dosagem , Adolescente , Adulto , Idoso , Feminino , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de TempoRESUMO
t(12;22)(p13;q12) is a rare but recurrent chromosomal abnormality involving the ETS transcription factor ETV6 and meningioma 1 (MN1) genes. In this study, we analyzed the clinical, cytogenetic, and molecular features of five new patients with the t(12;22)/MN1-EVT6 who presented with acute myeloid leukemia or chronic myelomonocytic leukemia. We subsequently reviewed the literature and identified seven additional cases reported with t(12;22)/MN1-EVT6. Our data suggest that neoplasms carrying the t(12;22)/MN1-ETV6, although rare, can commonly present as myeloid neoplasms at the initial diagnosis, including acute myeloid leukemia (n = 8), myelodysplastic syndrome (n = 2), and myelodysplastic/myeloproliferative neoplasms (n = 2). There were five men and seven women with a median age of 43 years (range, 15-63 years) at initial diagnosis. Cytogenetics revealed t(12;22) as the sole abnormality in five patients, with the remaining seven patients harboring additional chromosomal aberrations. Of the five patients who received known therapy regimens, all of them had poor response to the idarubicin/mitoxantrone + cytarabine regimen. Of the seven patients with follow-up information, six patients died with a median overall survival time of only 5 months (range, 1-12 months) after the emergence of t(12;22). In summary, patients with t(12;22) are frequently associated with myeloid neoplasms, poor response to chemotherapy, and inferior outcome.
Assuntos
Neoplasias da Medula Óssea/genética , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Repressoras/genética , Translocação Genética , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Neoplasias da Medula Óssea/patologia , Cromossomos Humanos Par 12 , Cromossomos Humanos Par 13 , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Transativadores , Adulto Jovem , Variante 6 da Proteína do Fator de Translocação ETSRESUMO
Most patients with polycythemia vera (PV) and half of essential thrombocythemia (ET) possess an activating JAK2V617F mutation. The objective of this study was to better define the effect of JAK2V617F mutant allele burden on clinical phenotypes in Chinese patients, especially thrombosis. By real-time polymerase chain reaction (RT-PCR), the JAK2V617F mutation burden was detected in 170 JAK2V617F-positive patients, including 54 PV and 116 ET. The results showed that JAK2V617F allele burden was higher in PV than in ET (P< 0.001). Higher percentage of patients had JAK2V617F allele burden over 20% in PV than in ET (68.5% VS 26.7%) (P< 0.001). In PV patients, higher JAK2V617F allele burden was observed in female (P< 0.05) and leukocytosis patients (WBC above 10 × 10(9)/L) (P< 0.001). Meanwhile, ET patients showed increased JAK2V617F allele burden in the group with higher hemoglobin (HGB above 150 g/L) (P< 0.05), leukocytosis (WBC above 10 × 10(9)/L) (P< 0.001), splenomegaly (P< 0.05) and thrombosis (P< 0.05). In conclusion, the JAK2V617F mutation allele burden is higher in Chinese patients with PV than ET. In PV patients, JAK2V617F mutation burden had influence on WBC counts. And the clinical characteristics of ET patients, such as WBC counts, hemoglobin level, splenomegaly and thrombosis, were influenced by JAK2V617F mutation burden. Male, high hemoglobin (HGB above 150 g/L), and increased JAK2V617F mutation burden (JAK2V617F allele burden ≥ 16.5%) were risks of thrombosis (P< 0.05) for ET patients by Logistic Regression.
Assuntos
Janus Quinase 2/genética , Policitemia Vera/genética , Trombocitemia Essencial/genética , Idoso , Alelos , China , Feminino , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Policitemia Vera/patologia , Polimorfismo de Nucleotídeo Único , Trombocitemia Essencial/patologia , Trombose/genética , Trombose/patologiaAssuntos
Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Quimioterapia de Indução , Leucemia Mieloide Aguda , Proteínas de Neoplasias/sangue , Adolescente , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Cariótipo , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Fatores de Transcrição MEF2/sangue , Masculino , Pessoa de Meia-Idade , Taxa de SobrevidaAssuntos
Leucemia Promielocítica Aguda , Proteínas de Fusão Oncogênica , Receptores do Ácido Retinoico , Fatores de Poliadenilação e Clivagem de mRNA , Feminino , Humanos , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patologia , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Receptores do Ácido Retinoico/genética , Receptores do Ácido Retinoico/metabolismo , Fatores de Poliadenilação e Clivagem de mRNA/genética , Fatores de Poliadenilação e Clivagem de mRNA/metabolismo , Receptor gama de Ácido RetinoicoAssuntos
Cromossomos Humanos Par 12/ultraestrutura , Cromossomos Humanos Par 4/ultraestrutura , Transtornos Mieloproliferativos/genética , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas c-ets/genética , RNA Longo não Codificante/genética , Proteínas Repressoras/genética , Translocação Genética , Cariótipo Anormal , Idoso , Medula Óssea/patologia , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 4/genética , Diagnóstico Diferencial , Éxons/genética , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Masculino , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/patologia , Variante 6 da Proteína do Fator de Translocação ETSRESUMO
BACKGROUND: This study was conducted to determine the antineoplastic activities of 5-aza-2'-deoxycytidine (decitabine; DAC) and all-trans retinoic acid (ATRA), administered either alone or in combination, on in vitro cultured SHI-1 cells as well as their effects on the expression of the tumor suppressor gene p16(INK4a) (p16) and the retinoic acid receptor (RAR)-ß. METHODS: Cell growth inhibition, differentiation and apoptosis were determined in SHI-1 cells treated with DAC and/or ATRA, and the combination index of the two compounds was calculated. Methylation of the p16 and RAR-ß genes in SHI-1 cells was detected by methylation-specific polymerase chain reaction (PCR). Real-time quantitative reverse transcriptase PCR was used to detect mRNA expression of the p16 and RAR-ß genes, and Western blot analysis was performed for protein expression. RESULTS: The drug combination had a synergistic effect on growth inhibition, differentiation and apoptosis of SHI-1 cells, and the effects of DAC and ATRA were dependent on time. DAC, either alone or in combination with ATRA, induced demethylation of the genes p16 and RAR-ß, whereas ATRA alone had no effect on methylation. The RAR-ß gene was reexpressed following DAC-ATRA combination treatment, and both agents had no effect on p16 expression. CONCLUSION: The results revealed that DAC used in combination with ATRA has significant clinical potential in the treatment of acute monocytic leukemia.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Leucemia Monocítica Aguda/tratamento farmacológico , Receptores do Ácido Retinoico/biossíntese , Azacitidina/agonistas , Azacitidina/análogos & derivados , Azacitidina/farmacologia , Linhagem Celular Tumoral , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Decitabina , Humanos , Leucemia Monocítica Aguda/metabolismo , Leucemia Monocítica Aguda/patologia , Tretinoína/agonistas , Tretinoína/farmacologiaRESUMO
The polycomb group BMI1 is proved to be crucial in malignant myeloid progression. However, the underlying mechanism of the action of BMI1 in myeloid malignant progression was not well characterized. In this study, we found that the patients of both myelodysplastic syndromes and chronic myeloid leukaemia with BMI1 overexpression had a higher risk in malignant myeloid progression. In vitro gene transfection studies showed that BMI1 inhibited cell myeloid and erythroid differentiation induced by 12-O-tetradecanoyl phorbol-13-acetate (TPA) and histone deacetylase inhibitor sodium butyrate respectively. BMI1 also resisted apoptosis induced by arsenic trioxide. Moreover, the transcript levels of Runx1 and Pten were down-regulated in Bmi1-transfected cells in company with histone deacetylation modification. By using chromatin immunoprecipitation (ChIP) collaborated with secondary generation sequencing and verified by ChIP-PCR, we found that BMI1 directly bound to the promoter region of Zmym3, which encodes a component of histone deacetylase-containing complexes. In addition, as one of the downstream target genes of this complex, c-fos was activated with increasing histone acetylation when ZMYM3 was suppressed in the Bmi1-transfected cells. These results suggested that BMI1 may reprogramme the histone acetylation profile in multiple genes through either indirect or direct binding effects which probably contributes to the malignant progression of myeloid progenitor cells.
Assuntos
Regulação Neoplásica da Expressão Gênica , Histonas/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Síndromes Mielodisplásicas/patologia , Proteínas Nucleares/genética , Complexo Repressor Polycomb 1/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Acetilação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose/efeitos dos fármacos , Western Blotting , Ácido Butírico/farmacologia , Estudos de Casos e Controles , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Imunoprecipitação da Cromatina , Feminino , Citometria de Fluxo , Antagonistas dos Receptores Histamínicos/farmacologia , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/metabolismo , Proteínas Nucleares/metabolismo , Complexo Repressor Polycomb 1/genética , Ligação Proteica , Proteínas Proto-Oncogênicas c-fos/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Acetato de Tetradecanoilforbol/análogos & derivados , Acetato de Tetradecanoilforbol/farmacologia , Adulto JovemAssuntos
Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/patologia , Proteínas de Fusão Oncogênica/genética , Receptores do Ácido Retinoico/genética , Receptor alfa de Ácido Retinoico/genética , Translocação Genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 17/genética , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem , Receptor gama de Ácido RetinoicoRESUMO
PURPOSE: To evaluate the efficacy of next-generation sequencing (NGS) in minimal-residual-disease (MRD) monitoring in Chinese patients with multiple myeloma (MM). METHODS: This study analyzed 60 Chinese MM patients. During MRD monitoring in these patients' post-therapy, clonal immunoglobulin heavy chain (IGH) rearrangements were detected via NGS using LymphoTrack assays. MRD monitoring was performed using NGS or next-generation flow cytometry (NGF), and the results were compared. Additionally, the sensitivity and reproducibility of the NGS method were assessed. RESULTS: The MRD detection range of the NGS method was 10-6-10-1, which suggested good linearity, with a Pearson correlation coefficient of 0.985 and a limit of detection of 10-6. Intra- and inter-assay reproducibility analyses showed that NGS exhibited 100% reproducibility with low variability in clonal cells. At diagnosis, unique clones were found in 42 patients (70.0%) with clonal IGH rearrangements, which were used as clonality markers for MRD monitoring post-therapy. Comparison of NGS and NGF for MRD monitoring showed 79.1% concordance. No samples that tested MRD-positive via NGF were found negative via NGS, indicating the higher sensitivity of NGS. MRD could be detected using NGS in 6 of 7 samples before autologous hematopoietic stem-cell transplantation, and 5 of them tested negative post-transplantation. In contrast, the NGF method could detect MRD in only 1 sample pre-transplantation. CONCLUSION: Compared with NGF, NGS exhibits higher sensitivity and reproducibility in MRD detection and can be an effective strategy for MRD monitoring in Chinese MM patients.
Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/genética , Leucemia Mieloide Aguda/genética , Neoplasias Primárias Múltiplas/genética , Proteínas de Fusão Oncogênica/genética , Proteína 1 Parceira de Translocação de RUNX1/genética , Cariótipo Anormal , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bandeamento Cromossômico , Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 15/ultraestrutura , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 17/ultraestrutura , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 21/ultraestrutura , Cromossomos Humanos Par 8/genética , Cromossomos Humanos Par 8/ultraestrutura , Células Clonais/química , Células Clonais/patologia , Humanos , Hibridização in Situ Fluorescente , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/tratamento farmacológico , Neoplasias Primárias Múltiplas/patologia , Células-Tronco Neoplásicas/química , Células-Tronco Neoplásicas/patologia , Reação em Cadeia da Polimerase em Tempo Real , Translocação GenéticaRESUMO
OBJECTIVE: To evaluate the possible mechanism of transcription factors B cell lymphoma 6 (Bcl-6) , forkhead/winged helix transcription factor 3 (Foxp3) and retinoic acid related orphan receptor (RORγt) in CD4(+) T cells for immuno-related hematocytopenia (IRH). METHODS: CD4(+) T cells were harvested from 40 IRH patients, 38 aplastic anemia subjects and 25 normal controls and separated by magnetic activated cell sorting (MACS). Then the expressions of transcription factors of Foxp3, RORγ and Bcl-6 in CD4(+) T cells were measured by real time fluorescent quantitative-polymerase chain reaction (QRT-PCR). RESULTS: Auto-antibody was detected on CD34(+) cells (67.5% (27/40) ), CD15(+) cells (65.0% (26/40)), GlyA(+) cells (75.0% (30/40) ), auto-antibody involving three, two or one myeloid cell were detected in 27.5% (11/40), 52.5% (21/40), 20.0% (8/40) of IRH patients. Compensatory increase of Foxp3 mRNA was found in IRH (0.124 (0.073-0.198) vs 0.071 (0.046-0.118), P < 0.05). The expression of Bcl-6 was higher (2.243 (0.854-4.544) vs 1.211 (0.131-2.816), P < 0.05). Compared to aplastic anemia, the expression of RORγt was lower in IRH (0.133 (0.068-0.189) vs 0.290 (0.138-0.480), P < 0.01) and the ratio of Treg/Th17 shifted to Th17 in patients with aplastic anemia (Foxp3/RORγt ratio,0.500 (0.240-0.795) vs 0.975 (0.483-1.416), P < 0.01). CONCLUSION: As one kind of bone marrow failures caused by autoantibody to bone marrow cells, IRH may occur due to a high expression of Bcl-6 in CD4(+) T cells, its immunopathogenesis is different from that of aplastic anemia.