RESUMO
BCR-ABL1 is in the center of chronic myeloid leukemia (CML) pathology, diagnosis and treatment, as confirmed by the success of tyrosine kinase inhibitor (TKI) therapy. However, additional mechanisms and events, many of which function independently of BCR-ABL1, play important roles, particularly in terms of leukemic stem cell (LSC) persistence, primary and secondary resistance, and disease progression. Promising therapeutic approaches aim to disrupt pathways which mediate LSC survival during successful TKI treatment, in the hope of improving long-term treatment-free-remission and perhaps provide a functional cure for some patients. Over the years through advances in sequencing technology frequent molecular aberrations in addition to BCR-ABL1 have been identified not only in advanced disease but also in chronic phase CML, often affecting epigenetic regulators such as ASXL1, DNMT3A and TET2. Analyses of serial samples have revealed various patterns of clonal evolution with some mutations preceding the BCR-ABL1 acquisition. Such mutations can be considered to be important co-factors in the pathogenesis of CML and could potentially influence therapeutic strategies in the future.
Assuntos
DNA (Citosina-5-)-Metiltransferases , Proteínas de Ligação a DNA , Epigênese Genética , Proteínas de Fusão bcr-abl , Regulação Leucêmica da Expressão Gênica , Leucemia Mielogênica Crônica BCR-ABL Positiva , Proteínas Proto-Oncogênicas , Proteínas Repressoras , DNA (Citosina-5-)-Metiltransferases/biossíntese , DNA (Citosina-5-)-Metiltransferases/genética , DNA Metiltransferase 3A , Proteínas de Ligação a DNA/biossíntese , Proteínas de Ligação a DNA/genética , Dioxigenases , Proteínas de Fusão bcr-abl/biossíntese , Proteínas de Fusão bcr-abl/genética , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/biossíntese , Proteínas Repressoras/genéticaAssuntos
Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , RNA Mensageiro/genética , RNA Neoplásico/genética , Adulto , Idoso , Transformação Celular Neoplásica/genética , Pontos de Quebra do Cromossomo , Feminino , Proteínas de Fusão bcr-abl/biossíntese , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/genética , RNA Mensageiro/biossíntese , RNA Neoplásico/biossíntese , Transcrição Gênica , Adulto JovemAssuntos
Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Idoso , Proteínas de Fusão bcr-abl/biossíntese , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RecidivaRESUMO
For patients with chronic myeloid leukemia, reverse transcription quantitative polymerase chain reaction is widely used in laboratories to quantify BCR-ABL1 fusion gene transcripts for disease management. Many efforts have been made to standardize the BCR-ABL1 testing assay, including the primary and secondary reference reagents, but the secondary standards have not been developed and used in the standardization program in China. With the use of armored RNA technology, armored RNA of BCR-ABL1 and control genes was manufactured to prepare the secondary reference material anchored to the World Health Organization primary reference calibrators for standardization of BCR-ABL1 testing assays. The secondary reference was sent to 30 laboratories in China for validation. Data from an external quality assessment after the standardization process were collected and analyzed as well. The assigned %BCR-ABL1/ABL1IS values of the four levels of the secondary material panels were 0.0118, 0.1345, 1.3808, and 19.4266, respectively. In validation trials, 70.0% (21/30) of laboratories obtained valid conversion factors for the BCR-ABL1 assay. All valid conversion factors from 11 international scale laboratories were equivalent to their respective previous values. External quality assessment data indicated that the accuracy and precision between laboratories were improved. Moreover, the quantity of the panels is abundant to be used as quality control samples for monitoring the shift of data. In this study, we established a secondary genetic reference panel for BCR-ABL1 quantification. This study will play a role in facilitating the worldwide dissemination of the international scale, especially in promoting the standardization of molecular monitoring in China.
Assuntos
Proteínas de Fusão bcr-abl , Regulação Leucêmica da Expressão Gênica , Reação em Cadeia da Polimerase Via Transcriptase Reversa/normas , China , Proteínas de Fusão bcr-abl/biossíntese , Proteínas de Fusão bcr-abl/genética , Humanos , Controle de Qualidade , Padrões de ReferênciaAssuntos
Transplante de Medula Óssea , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Proteínas de Fusão bcr-abl/genética , Transplante de Células-Tronco de Sangue Periférico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , RNA Mensageiro/genética , RNA Neoplásico/genética , Aloenxertos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas de Fusão bcr-abl/biossíntese , Humanos , Estimativa de Kaplan-Meier , Peso Molecular , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Inibidores de Proteínas Quinases/administração & dosagem , Recidiva , Estudos Retrospectivos , Fatores de Risco , Transcrição GênicaRESUMO
BCR-ABL1-negative myeloproliferative disorders and chronic myeloid leukaemia are haematologic malignancies characterised by single and mutually exclusive genetic alterations. Nevertheless, several patients co-expressing the JAK2V617F mutation and the BCR-ABL1 transcript have been described in the literature. We report the case of a 61-year-old male who presented with an essential thrombocythaemia phenotype and had a subsequent diagnosis of chronic phase chronic myeloid leukaemia. Colony-forming assays demonstrated the coexistence of 2 different haematopoietic clones: one was positive for the JAK2V617F mutation and the other co-expressed both JAK2V617F and the BCR-ABL1 fusion gene. No colonies displayed the BCR-ABL1 transcript alone. These findings indicate that the JAK2V617F mutation was the founding genetic alteration of the disease, followed by the acquisition of the BCR-ABL1 chimeric oncogene. Our data support the hypothesis that a heterozygous JAK2V617F clone may have favoured the bi-clonal nature of this myeloproliferative disorder, generating clones harbouring a second transforming genetic event.
Assuntos
Proteínas de Fusão bcr-abl , Regulação Enzimológica da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Janus Quinase 2 , Leucemia Mielogênica Crônica BCR-ABL Positiva , Mutação de Sentido Incorreto , Trombocitemia Essencial , Substituição de Aminoácidos , Ensaio de Unidades Formadoras de Colônias , Proteínas de Fusão bcr-abl/biossíntese , Proteínas de Fusão bcr-abl/genética , Humanos , Janus Quinase 2/biossíntese , Janus Quinase 2/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/enzimologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Trombocitemia Essencial/enzimologia , Trombocitemia Essencial/genética , Trombocitemia Essencial/patologiaRESUMO
The oncoprotein BCR-ABL1 triggers chronic myeloid leukemia. It is clear that the disease relies on constitutive BCR-ABL1 kinase activity, but not all the interactors and regulators of the oncoprotein are known. We describe and validate a Drosophila leukemia model based on inducible human BCR-ABL1 expression controlled by tissue-specific promoters. The model was conceived to be a versatile tool for performing genetic screens. BCR-ABL1 expression in the developing eye interferes with ommatidia differentiation and expression in the hematopoietic precursors increases the number of circulating blood cells. We show that BCR-ABL1 interferes with the pathway of endogenous dAbl with which it shares the target protein Ena. Loss of function of ena or Dab, an upstream regulator of dAbl, respectively suppresses or enhances both the BCR-ABL1-dependent phenotypes. Importantly, in patients with leukemia decreased human Dab1 and Dab2 expression correlates with more severe disease and Dab1 expression reduces the proliferation of leukemia cells. Globally, these observations validate our Drosophila model, which promises to be an excellent system for performing unbiased genetic screens aimed at identifying new BCR-ABL1 interactors and regulators in order to better elucidate the mechanism of leukemia onset and progression.
Assuntos
Animais Geneticamente Modificados , Proteínas de Fusão bcr-abl , Regulação Leucêmica da Expressão Gênica , Leucemia Mielogênica Crônica BCR-ABL Positiva , Animais , Animais Geneticamente Modificados/genética , Animais Geneticamente Modificados/metabolismo , Modelos Animais de Doenças , Drosophila melanogaster , Proteínas de Fusão bcr-abl/biossíntese , Proteínas de Fusão bcr-abl/genética , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologiaAssuntos
Proteínas de Fusão bcr-abl , Regulação Enzimológica da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Leucemia Mielogênica Crônica BCR-ABL Positiva , Cromossomo Filadélfia , Adulto , Proteínas de Fusão bcr-abl/biossíntese , Proteínas de Fusão bcr-abl/genética , Humanos , Isoenzimas/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/enzimologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , MasculinoRESUMO
BCR/ABL1-like acute lymphoblastic leukaemia (ALL) is a subgroup of B-lineage acute lymphoblastic leukaemia that occurs within cases without recurrent molecular rearrangements. Gene expression profiling (GEP) can identify these cases but it is expensive and not widely available. Using GEP, we identified 10 genes specifically overexpressed by BCR/ABL1-like ALL cases and used their expression values - assessed by quantitative real time-polymerase chain reaction (Q-RT-PCR) in 26 BCR/ABL1-like and 26 non-BCR/ABL1-like cases to build a statistical "BCR/ABL1-like predictor", for the identification of BCR/ABL1-like cases. By screening 142 B-lineage ALL patients with the "BCR/ABL1-like predictor", we identified 28/142 BCR/ABL1-like patients (19·7%). Overall, BCR/ABL1-like cases were enriched in JAK/STAT mutations (P < 0·001), IKZF1 deletions (P < 0·001) and rearrangements involving cytokine receptors and tyrosine kinases (P = 0·001), thus corroborating the validity of the prediction. Clinically, the BCR/ABL1-like cases identified by the BCR/ABL1-like predictor achieved a lower rate of complete remission (P = 0·014) and a worse event-free survival (P = 0·0009) compared to non-BCR/ABL1-like ALL. Consistently, primary cells from BCR/ABL1-like cases responded in vitro to ponatinib. We propose a simple tool based on Q-RT-PCR and a statistical model that is capable of easily, quickly and reliably identifying BCR/ABL1-like ALL cases at diagnosis.
Assuntos
Proteínas de Fusão bcr-abl , Regulação Leucêmica da Expressão Gênica , Modelos Biológicos , Leucemia-Linfoma Linfoblástico de Células Precursoras , Reação em Cadeia da Polimerase em Tempo Real , Adolescente , Adulto , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Proteínas de Fusão bcr-abl/biossíntese , Proteínas de Fusão bcr-abl/genética , Humanos , Lactente , Recém-Nascido , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Valor Preditivo dos Testes , Taxa de SobrevidaRESUMO
Chronic myeloid leukemia (CML) is a myeloproliferative disease caused by the BCR-ABL1 tyrosine kinase (TK). The development of TK inhibitors (TKIs) revolutionized the treatment of CML patients. However, TKIs are not effective to those at advanced phases when amplified BCR-ABL1 levels and increased genomic instability lead to secondary oncogenic modifications. Wiskott-Aldrich syndrome protein (WASP) is an important regulator of signaling transduction in hematopoietic cells and was shown to be an endogenous inhibitor of the c-ABL TK. Here, we show that the expression of WASP decreases with the progression of CML, inversely correlates with the expression of BCR-ABL1 and is particularly low in blast crisis. Enforced expression of BCR-ABL1 negatively regulates the expression of WASP. Decreased expression of WASP is partially due to DNA methylation of the proximal WASP promoter. Importantly, lower levels of WASP in CML advanced phase patients correlate with poorer overall survival (OS) and is associated with TKI response. Interestingly, enforced expression of WASP in BCR-ABL1-positive K562 cells increases the susceptibility to apoptosis induced by TRAIL or chemotherapeutic drugs and negatively modulates BCR-ABL1-induced tumorigenesis in vitro and in vivo. Taken together, our data reveal a novel molecular mechanism that operates in BCR-ABL1-induced tumorigenesis that can be used to develop new strategies to help TKI-resistant, CML patients in blast crisis (BC).
Assuntos
Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Proteínas de Fusão bcr-abl/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Proteína da Síndrome de Wiskott-Aldrich/metabolismo , Azacitidina/uso terapêutico , Carcinogênese/genética , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Resistencia a Medicamentos Antineoplásicos , Epigênese Genética , Proteínas de Fusão bcr-abl/biossíntese , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Regiões Promotoras Genéticas/genética , Inibidores de Proteínas Quinases/uso terapêutico , Transdução de Sinais/fisiologia , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Proteína da Síndrome de Wiskott-Aldrich/biossíntese , Proteína da Síndrome de Wiskott-Aldrich/genéticaAssuntos
Proteínas de Fusão bcr-abl/biossíntese , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Adolescente , Adulto , Assistência ao Convalescente , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Proteínas de Fusão bcr-abl/genética , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Masculino , Pessoa de Meia-Idade , Taxa de SobrevidaRESUMO
Sequential measurement of BCR-ABL1 mRNA levels by reverse transcription quantitative polymerase chain reaction (RT-qPCR) is embedded in the management of patients with chronic myeloid leukaemia (CML), and has played an important role in the remarkable improvement in patient outcomes seen in this disease. As a provider of external quality assessment (EQA) in this area, UK NEQAS for Leucocyte Immunophenotyping (UKNEQAS LI) has a unique perspective on the changing face of BCR-ABL1 testing in CML. To assess the impact of technical standardisation and the development of the International Scale (IS) upon the accuracy of BCR-ABL1 testing, we reviewed EQA trial data from 2007 to 2015. Comparison of participant results identified considerable variability at both high and low levels of disease, including therapeutically important decision points; however, results converted to the IS showed less variability compared to unconverted data sets. We also found that different methods of converting to the IS produce consistently different median results within UKNEQAS LI IS data sets. This data suggests that whilst the development of the IS has improved the comparability of results between centres, there is still the need for further improvement in the processes of converting raw results to the IS in order to fully realise the benefits of molecular monitoring of CML.
Assuntos
Biomarcadores Tumorais/genética , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Biomarcadores Tumorais/biossíntese , Proteínas de Fusão bcr-abl/biossíntese , Humanos , Imunofenotipagem/métodos , Imunofenotipagem/normas , Cooperação Internacional , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Garantia da Qualidade dos Cuidados de Saúde , RNA Mensageiro/genética , RNA Neoplásico/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodosRESUMO
OBJECTIVES: Imatinib (Glivec) has been covered by critical disease insurance for treatment of chronic myeloid leukemia (CML) in Jiangsu province of China since 2013. Further, free molecular monitoring has been provided to patients at top clinical centers as part of a pilot study that has changed the local treatment pattern and outcomes of patients with CML. This study evaluates the impact of medical insurance coverage and the molecular monitoring frequency on outcomes of patients with CML treated at a central hospital in Jiangsu, China, according to patient-level data. METHODS: The study investigated 335 CML patients receiving medical treatment in a central hospital between January 1, 2011 and December 31, 2014. Demographic and clinical characteristics were extracted from the patients' clinical records. Univariate and multivariate analyses using the logistic regression model were performed to identify the differences in outcomes of major molecular response (MMR) or complete cytogenetic response (CCyR) between patients who were insured vs uninsured, or between patients with frequency of PCR monitoring ≤2 times vs ≥3 times per year. RESULTS: Both the achievement of MMR (BCR-ABLIS ≤0.1%) (50.4% vs 37.5%) and CCyR (80.7% vs 62.8%) at 12 months have shown significant differences that favored patients with insurance coverage of imatinib, while there was no significant difference in the outcome of BCR-ABLIS ≤1% between insured and non-insured groups (56.0% vs 51.3%) at 6 months. The long-term results at 24 months demonstrated that there was a statistically significant difference in MMR rates between the group with 3 or more PCR monitoring tests per year and the group of patients with 2 or less PCR tests per year (76.9% vs 52.2%). CONCLUSIONS: The study findings suggest that CML patients benefit from insurance coverage of imatinib and higher frequency (≥3) of regularly scheduled molecular monitoring PCR in China.
Assuntos
Antineoplásicos/economia , Antineoplásicos/uso terapêutico , Mesilato de Imatinib/economia , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Adulto , Fatores Etários , China , Feminino , Proteínas de Fusão bcr-abl/biossíntese , Proteínas de Fusão bcr-abl/efeitos dos fármacos , Testes Hematológicos , Humanos , Cobertura do Seguro/economia , Cobertura do Seguro/estatística & dados numéricos , Seguro Saúde/economia , Seguro Saúde/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/economia , Inibidores de Proteínas Quinases/uso terapêutico , Fatores SexuaisAssuntos
Proteínas de Fusão bcr-abl , Leucemia Mielogênica Crônica BCR-ABL Positiva , RNA Mensageiro , RNA Neoplásico , Proteínas de Fusão bcr-abl/biossíntese , Proteínas de Fusão bcr-abl/genética , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genéticaRESUMO
INTRODUCTION: The hallmark of chronic myeloid leukemia (CML) is the presence of Philadelphia chromosome, its resultant fusion transcript (BCR-ABL1), and fusion protein (p210). Alternate breakpoints in BCR (m-bcr, µ-bcr, and others) or ABL1 result in the expression of few rare fusion transcripts (e19a2, e1a2, e13a3, e14a3) and fusion proteins (p190, p200, p225) whose exact clinical significance remains to be determined. METHODS: Our study was designed to determine the type and frequency of BCR-ABL1 fusion transcripts in 1260 CML patients and to analyze the prognosis and treatment response in patients harboring rare BCR-ABL1 fusion transcripts. RESULTS: The frequency of various BCR-ABL1 fusion transcripts was as follows: e14a2 (60%), e13a2 (34.3%), e1a2 (1.2%), e1a2 + e13a2 (2.0%), e1a2 + e14a2 (1.8%), e19a2 (0.3%), and e14a3 (0.3%). CML patients with e1a2 transcripts had higher rates of disease progression, resistance, or suboptimal response to imatinib and failed to achieve major molecular response. CONCLUSION: Characterization of the specific fusion transcript in CML patients is important owing to the difference in prognosis and response to therapy in addition to the conventional need for monitoring treatment response. CML patients with e1a2 transcripts have to be closely monitored due to the high incidence of disease progression and treatment resistance/failure.
Assuntos
Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Intervalo Livre de Doença , Feminino , Proteínas de Fusão bcr-abl/biossíntese , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Masculino , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Taxa de SobrevidaRESUMO
Point mutations in the ABL1 kinase domain are an important mechanism of resistance to tyrosine kinase inhibitors (TKI) in BCR-ABL1-positive and, as recently shown, BCR-ABL1-like leukemias. The cell line Ba/F3 lentivirally transduced with mutant BCR-ABL1 constructs is widely used for in vitro sensitivity testing and response prediction to tyrosine kinase inhibitors. The transposon-based Sleeping Beauty system presented offers several advantages over lentiviral transduction including the absence of biosafety issues, faster generation of transgenic cell lines, and greater efficacy in introducing large gene constructs. Nevertheless, both methods can mediate multiple insertions in the genome. Here we show that multiple BCR-ABL1 insertions result in elevated IC50 levels for individual TKIs, thus overestimating the actual resistance of mutant subclones. We have therefore established flow-sorting-based fractionation of BCR-ABL1-transformed Ba/F3 cells facilitating efficient enrichment of cells carrying single-site insertions, as demonstrated by FISH-analysis. Fractions of unselected Ba/F3 cells not only showed a greater number of BCR-ABL1 hybridization signals, but also revealed higher IC50 values for the TKIs tested. The data presented highlight the need to carefully select transfected cells by flow-sorting, and to control the insertion numbers by FISH and real-time PCR to permit unbiased in vitro testing of drug resistance.
Assuntos
Proteínas de Fusão bcr-abl/biossíntese , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Animais , Linhagem Celular Tumoral , Elementos de DNA Transponíveis , Proteínas de Fusão bcr-abl/genética , Humanos , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , CamundongosRESUMO
Despite the efficacy and safety of dasatinib treatment for chronic-phase chronic myeloid leukemia (CML-CP), adverse effects such as pleural effusion (PE) are still a serious concern. We determined the clinical significance of PE incidence using patient data derived from the D-First clinical study. In the present study, chest radiography and quantification of specific lymphocyte subsets were performed routinely after initiation of dasatinib treatment. Among 52 patients with newly diagnosed CML-CP, 17 (33%) developed PE within 18 months after initial dasatinib administration, but all cases were moderate (Grade 1, 10 patients; Grade 2, 7 patients). CD56+ lymphocyte counts at 1 month correlated significantly with the incidence of PE, whereas lymphocytosis did not. The major molecular response (MMR) rate at 3 months (although not at later times) was significantly higher in PE-positive patients than PE-negative patients (59% versus 24%, respectively; P=0.013). Deep molecular response rates did not differ significantly between the PE groups at any time point during the observation period. Our results suggest that an immune-mediated mechanism involving natural killer cells underlies the development of PE in patients receiving dasatinib for 18 months. This mechanism likely promotes transient tumor regression in patients newly diagnosed with CML-CP.
Assuntos
Dasatinibe/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Derrame Pleural/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Dasatinibe/administração & dosagem , Feminino , Proteínas de Fusão bcr-abl/biossíntese , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Mesilato de Imatinib/efeitos adversos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/patologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/complicações , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Derrame Pleural/induzido quimicamente , Derrame Pleural/genética , Derrame Pleural/patologia , Inibidores de Proteínas QuinasesRESUMO
The most common breakpoint cluster region gene-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL) transcripts in chronic myeloid leukemia (CML) are e13a2 (b2a2) and e14a2 (b3a2). The impact of the type of transcript on response and survival after initial treatment with different tyrosine kinase inhibitors is unknown. This study involved 481 patients with chronic phase CML expressing various BCR-ABL transcripts. Two hundred patients expressed e13a2 (42%), 196 (41%) expressed e14a2, and 85 (18%) expressed both transcripts. The proportion of patients with e13a2, e14a2, and both achieving complete cytogenetic response at 3 and 6 months was 59%, 67%, and 63% and 73%, 81%, and 82%, respectively, whereas major molecular response rates were 27%, 49%, and 50% at 3 months, 42%, 67%, and 70% at 6 months, and 55%, 83%, and 76% at 12 months, respectively. Median (international scale) levels of transcripts e13a2, e14a2, and both at 3 months were 0.2004, 0.056, and 0.0612 and at 6 months were 0.091, 0.0109, and 0.0130, respectively. In multivariate analysis, e14a2 and both predicted for optimal responses at 3, 6, and 12 months. The type of transcript also predicted for improved probability of event-free (P = .043; e14a2) and transformation-free survival (P = .04 for both). Compared to e13a2 transcripts, patients with e14a2 (alone or with coexpressed e13a2) achieved earlier and deeper responses, predicted for optimal European Leukemia Net (ELN) responses (at 3, 6, and 12 months) and predicted for longer event-free and transformation-free survival.
Assuntos
Proteínas de Fusão bcr-abl/biossíntese , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Inibidores de Proteínas Quinases/administração & dosagem , RNA Mensageiro/biossíntese , RNA Neoplásico/biossíntese , Adulto , Intervalo Livre de Doença , Feminino , Seguimentos , Proteínas de Fusão bcr-abl/genética , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/enzimologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Neoplásico/genética , Taxa de SobrevidaRESUMO
Imatinib and other tyrosine kinase inhibitors (TKI) have improved treatment of chronic myelogenous leukemia (CML); however, most patients are not cured. Deeper mechanistic understanding may improve TKI combination therapies to better control the residual leukemic cell population. In analyzing our patients' data, we found that many patients who otherwise responded well to imatinib therapy still showed variations in their BCR-ABL transcripts. To investigate this phenomenon, we applied a mathematical model that integrates CML and an autologous immune response to the patients' data. We define an immune window or a range of leukemic loads for which the autologous immune system induces an improved response. Our modeling results suggest that, at diagnosis, a patient's leukemic load is able to partially or fully suppress the autologous immune response developed in a majority of patients, toward the CML clone(s). Imatinib therapy drives the leukemic population into the "immune window," allowing the patient's autologous immune cells to expand and eventually mount an efficient recognition of the residual leukemic burden. This response drives the leukemic load below this immune window, allowing the leukemic population to partially recover until another weaker immune response is initiated. Thus, the autologous immune response may explain the oscillations in BCR-ABL transcripts regularly observed in patients on imatinib.
Assuntos
Antineoplásicos/farmacologia , Simulação por Computador , Proteínas de Fusão bcr-abl/biossíntese , Regulação Neoplásica da Expressão Gênica/imunologia , Mesilato de Imatinib/farmacologia , Vigilância Imunológica , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Modelos Biológicos , Células-Tronco Neoplásicas/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Transcrição Gênica/imunologia , Antineoplásicos/uso terapêutico , Diferenciação Celular , Células Clonais/patologia , Proteínas de Fusão bcr-abl/genética , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Células-Tronco Neoplásicas/imunologia , Inibidores de Proteínas Quinases/uso terapêutico , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Indução de Remissão , Resultado do Tratamento , Carga TumoralRESUMO
Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is triggered by BCR/ABL and SRC family tyrosine kinases. They interact with each other and subsequently activate downstream growth-signaling pathways, including Raf/MEK/ERK, Akt/mTOR, and STAT5 pathways. Although imatinib is the standard treatment for Ph+ leukemia, response rate of Ph+ ALL to imatinib is low, relapse is frequent and quick. Studies have documented the potential anti-tumor activities of curcumin. However, whether curcumin can be used in the therapy for Ph+ ALL remains obscure. Here, we reported that curcumin induced apoptosis by inhibition of AKT/mTOR and ABL/STAT5 signaling, down-regulation of BCR/ABL expression, and induction of the BCL2/BAX imbalance. Curcumin exerted synergetic anti-leukemia effects with imatinib by inhibition of the imatinib-mediated overactivation of AKT/mTOR signaling and down-regulation of BCR/ABL gene expression. In primary samples from Ph+ ALL patients, curcumin inhibited cellular proliferation and down-regulated constitutive activation of growth-signaling pathways not only in newly diagnosed patients but also in imatinib-resistant patients. In Ph+ ALL mouse models, curcumin exhibited synergetic anti-leukemia effects with imatinib. These results demonstrated that curcumin might be a promising agent for Ph+ ALL patients.