RESUMO
BACKGROUND: Acute promyelocytic leukemia (APL) is the sub-type of Acute myeloid leukemia (AML) which is described by differentiation block at promyelocytic stage and t(15; 17) translocation with All trans retinoic acid (ATRA) and arsenic trioxide (ATO) as standard treatments. Chronic myeloid leukemia (CML) translocation t (19; 22) causes a rise in granulocytes and their immature precursors in the blood. Different mutations cause resistance to first-line tyrosine kinase therapies in CML. Beside drug resistance, leukemia stem cells (LSC) are critical resources for relapse and resistance in APL and CML. The drug toxicity and resistant profile associated with LSC and current therapeutics of APL and CML necessitate the development of new therapies. Imidazoles are heterocyclic nitrogen compounds with diverse cellular actions. The purpose of this research was to assess the anti-leukemic properties of four novel imidazole derivatives including L-4, L-7, R-35, and R-NIM04. METHODS AND RESULTS: Pharmacological and biochemical approaches were used which showed that all four imidazole derivatives interfere with the NB4 cells proliferation, an APL cell line, while only L-7 exhibit anti-proliferative activity against K562 cells, a CML cell line. The anti-proliferative effect of imidazole derivatives was linked to apoptosis induction. Further real-time polymerase chain reaction (RT-PCR) analysis revealed downregulation of AXL-Receptor Tyrosine Kinase (AXL-RTK) and target genes of Wnt/beta-catenin pathway like c-Myc, Axin2 and EYA3. An additive effect was observed after combinatorial treatment of L-7 with standard drugs ATRA or Imatinib on the proliferation of NB4 and K562 cells respectively which was related to further downregulation of target genes of Wnt/beta catenin pathway. CONCLUSION: Imidazole derivatives significantly reduce proliferation of NB4 and K562 cells by inducing apoptosis, down regulating of AXL-RTK and Wnt/ß-catenin target genes.
Assuntos
Apoptose , Proliferação de Células , Imidazóis , Humanos , Imidazóis/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Células K562 , Receptor Tirosina Quinase Axl , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/patologia , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas/genética , Leucemia Mieloide/tratamento farmacológico , Leucemia Mieloide/patologia , Leucemia Mieloide/metabolismo , Leucemia Mieloide/genética , Via de Sinalização Wnt/efeitos dos fármacosRESUMO
Since the identification of the TTMV::RARA fusion in pediatric cases resembling acute promyelocytic leukemia (APL) by Astolfi et al. in 2021, several similar cases have been reported worldwide. In this report, we present a case of relapsed APL in an adolescent patient, who exhibited the TTMV::RARA fusion gene. This patient exhibited extensive central nervous system involvement and experienced bone marrow necrosis during disease recurrence. Despite achieving complete remission after re-induction chemotherapy, the patient experienced a rapid second relapse, highlighting the extremely aggressive nature of this subtype. These clinical manifestations contribute to the growing recognition of this rare disease.
Assuntos
Medula Óssea , Leucemia Promielocítica Aguda , Necrose , Humanos , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/patologia , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/genética , Adolescente , Medula Óssea/patologia , Proteínas de Fusão Oncogênica/genética , Masculino , Recidiva , Receptor alfa de Ácido Retinoico/genética , Sistema Nervoso Central/patologiaRESUMO
N-glycosylation is a highly heterogeneous post-translational modification that modulates protein function. Defects in N-glycosylation are directly linked to various human diseases. Despite the importance of quantifying N-glycans with high precision, existing glycoinformatics tools are limited. Here, we developed nQuant, a glycoinformatics tool that enables label-free and isotopic labeling quantification of N-glycomics data obtained via LC-MS/MS, ensuring a low false quantitation rate. Using the label-free quantification module, we profiled the N-glycans released from purified glycoproteins and HEK293 cells as well as the dynamic changes of N-glycosylation during mouse corpus callosum development. Through the isotopic labeling quantification module, we revealed the dynamic changes of N-glycans in acute promyelocytic leukemia cells after all-trans retinoic acid treatment. Taken together, we demonstrate that nQuant enables fast and precise quantitative N-glycomics.
Assuntos
Glicômica , Polissacarídeos , Humanos , Glicômica/métodos , Animais , Células HEK293 , Polissacarídeos/análise , Polissacarídeos/química , Polissacarídeos/metabolismo , Camundongos , Espectrometria de Massas em Tandem , Glicosilação , Glicoproteínas/análise , Glicoproteínas/metabolismo , Glicoproteínas/química , Cromatografia Líquida , Tretinoína/metabolismo , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patologiaRESUMO
INTRODUCTION: Acute promyelocytic leukemia (APL) is mainly due to the chromosome translocation t(15; 17) (q22; q12), leading to the formation of PML-RARα fusion protein. However, some patients carried rare translocation involving RARα gene, and they were referred to as variant APL caused by the RAR family (RARα, RARB, and RARG) and partner genes. PLZF-RARα was a rare type of molecular genetic abnormality with unfavorable prognosis that has been reported in few cases in variant APL. Knowledge of PLZF-RARα (+) APL treatment remains limited understood. CASE REPORT: We presented a case of variant APL in a 47-year-old female, who was PLZF-RARα positive detected by reverse transcription polymerase chain reaction (RT-PCR). The patient did not respond to all-trans retinoic acid (ATRA), idarubicin, and arsenic trioxide (As2O3) combined induction chemotherapy. Then, the patient was treated with Venetoclax combining with decitabine as the salvage therapy and achieved morphological remission and PLZF/RARα gene negative. CONCLUSION: Venetoclax combining with decitabine can be used as an effective therapy in the PLZF-RARα positive APL.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Compostos Bicíclicos Heterocíclicos com Pontes , Decitabina , Leucemia Promielocítica Aguda , Proteínas de Fusão Oncogênica , Sulfonamidas , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/genética , Feminino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Decitabina/uso terapêutico , Decitabina/administração & dosagem , Sulfonamidas/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Azacitidina/uso terapêuticoRESUMO
INTRODUCTION: There is currently no standard treatment for relapsed and arsenic trioxide (ATO)-resistant acute promyelocytic leukemia (APL). Here, we report a case series of realgar-indigo naturalis formula (RIF) for the successful treatment of patients with relapsed and ATO-resistant APL. CASE PRESENTATION: Two patients in the first relapse and one in the second relapse failed to achieve hematologic complete remission (HCR) when reinduced by ATO; the other five patients progressed to relapse during ATO-based regimens for post-remission therapy. These eight patients received RIF in three doses per day totaling 130 mg/kg (≤ 30 pills) as induction therapy and achieved HCR at a median time of 46.5 days. They received 5 years of post-remission therapy, which consisted of combined chemotherapy followed by RIF. During this period, the patients did not experience renal dysfunction or QT interval prolongation. At the last follow-up, three patients survived without relapse, two patients survived with a second or third relapse and third or fourth remission, and the other three patients relapsed for a third or fourth time and died. The 5-year overall survival and event-free survival rates were 75.0% (95% confidence interval [CI]: 31.5-93.1) and 37.5% (95% CI: 5.6-71.7), respectively. CONCLUSION: RIF for induction therapy and RIF combined with chemotherapy for post-remission therapy may represent an effective and safe protocol for the treatment of patients with relapsed and ATO-resistant APL. Please cite this article as: Fang YG, Huang SL, Chen NN. Realgar-indigo naturalis formula for the treatment of patients with relapsed and arsenic trioxide-resistant acute promyelocytic leukemia: a case series. J Integr Med. 2024; 22(5): 614-620.
Assuntos
Trióxido de Arsênio , Resistencia a Medicamentos Antineoplásicos , Medicamentos de Ervas Chinesas , Leucemia Promielocítica Aguda , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Trióxido de Arsênio/uso terapêutico , Trióxido de Arsênio/administração & dosagem , Masculino , Adulto , Pessoa de Meia-Idade , Feminino , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Medicamentos de Ervas Chinesas/uso terapêutico , Medicamentos de Ervas Chinesas/administração & dosagem , Recidiva , Indução de Remissão , Antineoplásicos/uso terapêutico , Adulto JovemRESUMO
In acute promyelocytic leukemia (APL), the promyelocytic leukemia-retinoic acid receptor alpha (PML/RARα) fusion protein destroys PML nuclear bodies (NBs), leading to the formation of microspeckles. However, our understanding, largely learned from morphological observations, lacks insight into the mechanisms behind PML/RARα-mediated microspeckle formation and its role in APL leukemogenesis. This study presents evidence uncovering liquid-liquid phase separation (LLPS) as a key mechanism in the formation of PML/RARα-mediated microspeckles. This process is facilitated by the intrinsically disordered region containing a large portion of PML and a smaller segment of RARα. We demonstrate the coassembly of bromodomain-containing protein 4 (BRD4) within PML/RARα-mediated condensates, differing from wild-type PML-formed NBs. In the absence of PML/RARα, PML NBs and BRD4 puncta exist as two independent phases, but the presence of PML/RARα disrupts PML NBs and redistributes PML and BRD4 into a distinct phase, forming PML/RARα-assembled microspeckles. Genome-wide profiling reveals a PML/RARα-induced BRD4 redistribution across the genome, with preferential binding to super-enhancers and broad-promoters (SEBPs). Mechanistically, BRD4 is recruited by PML/RARα into nuclear condensates, facilitating BRD4 chromatin binding to exert transcriptional activation essential for APL survival. Perturbing LLPS through chemical inhibition (1, 6-hexanediol) significantly reduces chromatin co-occupancy of PML/RARα and BRD4, attenuating their target gene activation. Finally, a series of experimental validations in primary APL patient samples confirm that PML/RARα forms microspeckles through condensates, recruits BRD4 to coassemble condensates, and co-occupies SEBP regions. Our findings elucidate the biophysical, pathological, and transcriptional dynamics of PML/RARα-assembled microspeckles, underscoring the importance of BRD4 in mediating transcriptional activation that enables PML/RARα to initiate APL.
Assuntos
Proteínas de Ciclo Celular , Leucemia Promielocítica Aguda , Proteínas de Fusão Oncogênica , Fatores de Transcrição , Humanos , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/patologia , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Fusão Oncogênica/metabolismo , Proteínas de Fusão Oncogênica/genética , Linhagem Celular Tumoral , Regulação Leucêmica da Expressão Gênica , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Proteína da Leucemia Promielocítica/metabolismo , Proteína da Leucemia Promielocítica/genética , Separação de Fases , Proteínas que Contêm BromodomínioRESUMO
Promyelocytic leukemia (PML) nuclear bodies (PML-NBs) are core-shell-type membrane-less organelles typically found in the nucleus of mammalian somatic cells but are absent in mouse oocytes. Here, we deliberately induced the assembly of PML-NBs by injecting mRNA encoding human PML protein (hPML VI -sfGFP) into oocytes and investigated their impact on fertilization in which oocyte/embryos undergo multiple types of stresses. Following nuclear membrane breakdown, preassembled hPML VI -sfGFP mRNA-derived PML-NBs (hmdPML-NBs) persisted in the cytoplasm of oocytes, forming less-soluble debris, particularly under stress. Parthenogenetic embryos that successfully formed pronuclei were capable of removing preassembled hmdPML-NBs from the cytoplasm while forming new hmdPML-NBs in the pronucleus. These observations highlight the beneficial aspect of the PML-NB-free nucleoplasmic environment and suggest that the ability to eliminate unnecessary materials in the cytoplasm of metaphase oocytes serves as a potential indicator of the oocyte quality.
Assuntos
Oócitos , Proteína da Leucemia Promielocítica , Oócitos/metabolismo , Animais , Camundongos , Proteína da Leucemia Promielocítica/metabolismo , Proteína da Leucemia Promielocítica/genética , Feminino , Humanos , Corpos de Inclusão Intranuclear/metabolismo , Divisão Celular Assimétrica , Citoplasma/metabolismo , Núcleo Celular/metabolismo , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patologia , Leucemia Promielocítica Aguda/genéticaRESUMO
INTRODUCTION: Acute promyelocytic leukemia (APL) is a distinct form of acute myeloid leukemia characterized by the presence of t(15;17)(q24;21) and the PML:RARA gene fusion. Frontline use of intravenous arsenic trioxide (i.v.-ATO) and all-trans retinoic acid (ATRA) has vastly improved cure rates in APL. Researchers in Hong Kong invented the oral formulation of ATO (oral-ATO) and have confirmed a bioavailability comparable to i.v.-ATO. A plethora of studies have confirmed the safety and efficacy of oral-ATO-based regimens in the frontline and relapsed setting. AREAS COVERED: Aspects on the development of oral-ATO-based regimens for APL in the frontline and relapsed setting are discussed. The short-term and long-term safety and efficacy of oral-ATO-based regimens are discussed. The frontline use of oral-ATO in combination with ATRA and ascorbic acid (AAA) induction in a 'chemotherapy-free' is highlighted. EXPERT OPINION: Current and ongoing data on the use of oral-ATO-based regimens in APL support the use of oral-ATO as an alternative to i.v.-ATO allowing a more convenient and economical approach to the management of APL.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Trióxido de Arsênio , Ácido Ascórbico , Leucemia Promielocítica Aguda , Óxidos , Tretinoína , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/diagnóstico , Tretinoína/uso terapêutico , Tretinoína/administração & dosagem , Trióxido de Arsênio/uso terapêutico , Trióxido de Arsênio/administração & dosagem , Administração Oral , Ácido Ascórbico/uso terapêutico , Ácido Ascórbico/administração & dosagem , Óxidos/uso terapêutico , Óxidos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Arsenicais/uso terapêutico , Arsenicais/administração & dosagem , Resultado do TratamentoRESUMO
Acute promyelocytic leukemia (APL), a distinctive subtype of acute myeloid leukemia (AML), is characterized by the t(15; 17) translocation forming the PML-RARα fusion protein. Recent studies have revealed a crucial role of retinoid X receptor α (RXRα) in PML-RARα's tumorigenesis. This necessitates the development of dual RARα and RXRα targeting compounds for treating APL. Here, we developed a pair of brominated retinoid isomers, 5a and 5b, exhibiting RARα agonistic selectivity among the RAR subtypes and RXRα partial agonistic activities. In the treatment of APL cells, low doses (RARα activation range) of 5a and 5b degrade PML-RARα and strongly induce differentiation, while higher doses (RXRα activation range) induce G2/M arrest and apoptosis in both all-trans retinoic acid (ATRA)-sensitive and resistant cells. We replaced the bromine in 5a with chlorine or iodine to obtain compounds 7 or 8a. Interestingly, the chlorinated compound 7 tends to activate RXRα and induce G2/M arrest and apoptosis, while the iodinated compound 8a tends to activate RARα and induce differentiation. Together, our work underscores several advantages and characteristics of halogens in the rational design of RARα and RXRα ligands, offering three promising drug candidates for treating both ATRA-sensitive and resistant APL.
Assuntos
Antineoplásicos , Leucemia Promielocítica Aguda , Receptor alfa de Ácido Retinoico , Receptor X Retinoide alfa , Retinoides , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/patologia , Leucemia Promielocítica Aguda/metabolismo , Receptor alfa de Ácido Retinoico/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Retinoides/farmacologia , Retinoides/química , Retinoides/síntese química , Receptor X Retinoide alfa/metabolismo , Receptor X Retinoide alfa/antagonistas & inibidores , Relação Estrutura-Atividade , Estrutura Molecular , Relação Dose-Resposta a Droga , Apoptose/efeitos dos fármacos , Halogenação , Ensaios de Seleção de Medicamentos Antitumorais , Proliferação de Células/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular TumoralRESUMO
In acute promyelocytic leukemia (APL), the combination treatment of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) appears to have a synergistic effect. Due to this synergism, differentiation syndrome (DS) in APL assumes a distinct identity separate from the formerly known ATRA syndrome, with distinct temporal patterns, diagnostic parameters, and clinical behavior. We retrospectively evaluated single-center data of years 2013-2022. Patients with newly diagnosed APL were categorized into three groups (16 patients in ATRA/ATO standard-risk group, 3 patients in ATRA/chemotherapy standard-risk group, and 5 patients in ATRA/chemotherapy high-risk group). Our aim was to analyze leukocytosis, signs of DS, and hepatic impairment within the first 25 days of treatment. The incidence of DS in the ATRA/ATO SR group was 43.8â¯%, with a median of 4 days and 2 days from ATRA and ATO initiation, respectively. This group also exhibited higher peak levels of leukocytosis 34.5 (6.0-113.4) x109/L (p = 0.0809). ALT elevation was more prevalent in the ATRA/ATO SR group (93.75â¯%), with 68.75â¯% grade 3-4 elevations (p = 0.0094). Importantly, all patients in this group had ALT levels that returned to normal during the subsequent consolidations. These findings suggest hepatopathy as a potential manifestation of ATRA/ATO induced leukocyte differentiation and/or DS. Diverse differentiation patterns were identified within the ATRA/ATO group, classifying patients into three distinct subgroups based on the concurrent dynamics of leukocytes and ALT levels, illustrating simultaneous, sequential, and divergent elevation patterns. These emphasize the different distribution of differentiation (organs vs. peripheral blood). We introduced real-world data and advocated for reevaluation of the current DS definition and associated diagnostic thresholds. Our study, conducted in a small country with a limited number of APL patients, acknowledges the inherent constraints in sample size. Further investigations with larger patient cohorts are warranted to validate and reinforce the outcomes observed in our study.
Assuntos
Trióxido de Arsênio , Leucemia Promielocítica Aguda , Tretinoína , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Trióxido de Arsênio/efeitos adversos , Trióxido de Arsênio/uso terapêutico , Trióxido de Arsênio/administração & dosagem , Tretinoína/efeitos adversos , Tretinoína/administração & dosagem , Tretinoína/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Estudos Retrospectivos , Idoso , Diferenciação Celular , Adulto Jovem , Leucocitose/induzido quimicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Síndrome , AdolescenteRESUMO
OBJECTIVE: To describe the prognostic variables and course of paediatric acute promyelocytic leukaemia (APL) in Pakistan. STUDY DESIGN: Cohort study. Place and Duration of the Study: Department of Paediatric Oncology, Combined Military Hospital, Rawalpindi, Pakistan, from January 2012 to December 2022. METHODOLOGY: Patients aged 1-15 years, clinically confirmed APL with promyelocytic leukaemia- retinoic acid receptor alpha (PML-RARA) were enrolled. Initial admission included a thorough examination, recording demographic and clinical data, reporting time, prior treatment, and socioeconomic status. Statistical analysis used SPSS 25.0, with significance at p <0.05. RESULTS: This study included 50 cases of APL. Out of which, 32 (64%) were males and 18 (34%) were females. The mean age at diagnosis was 7.02 ± 3.86 years. Pallor (96%) and fever (88%) were common presentations. The average white blood cell count was 28.70 ± 35.39 x109/L. Treatment protocols include 48% International Consortium for Childhood (ICC)-APL, and 52% arsenic trioxide (ATO). High-risk cases were 54%. Neutropenic fever and differentiation syndrome were common induction complications. Delays over one month increased induction deaths (6.7 to 35%, p = 0.011), reducing disease-free survival (DFS), (76.7 to 35%, p = 0.001), and overall survival (OS), (80 to 45%, p = 0.007). After 40.90 ± 45.19 months' follow-up, 10-year OS and DFS were 66.0% and 60.0%, respectively. The best OS and DFS, at 80%, were observed in standard-risk cases treated with ATO. CONCLUSION: Neutropenic fever and bleeding were the primary causes of mortality in paediatric APL induction. Treatment delay was a key prognostic factor. ATO-based therapy offered safer, improved DFS, and OS suitable for primary healthcare settings. KEY WORDS: Acute promyelocytic leukaemia, Chemotherapy, Neutropenic fever.
Assuntos
Leucemia Promielocítica Aguda , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/mortalidade , Masculino , Feminino , Paquistão/epidemiologia , Criança , Pré-Escolar , Adolescente , Lactente , Prognóstico , Estudos de Coortes , Trióxido de Arsênio/uso terapêutico , Resultado do Tratamento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
OBJECTIVE: To analyze the correlation between serum fibronectin 3 (Ficolin-3) levels and early severe bleeding in newly diagnosed acute promyelocytic leukemia (APL) patients. METHODS: A total of 125 patients with newly diagnosed APL admitted to Shanxi Bethune Hospital from January 2020 to August 2023 were selected. All patients were given all-trans retinoic acid+arsenic for induction therapy. The severe bleeding events within 30 days of induction therapy (assessed by WHO bleeding score, grade 0, grade 1 and grade 2 were no bleeding or mild bleeding, grade 3 and grade 4 were severe or fatal bleeding) were used as observation endpoints. The serum Ficolin-3 levels was dected by ELISA method, baseline data and other laboratory indicators were counted, and the correlation between serum Ficolin-3 levels and early severe bleeding in newly diagnosed APL patients was analyzed. RESULTS: 23 out of 125 APL patients experienced early severe bleeding during induction therapy, including 13 cases of grade 3 bleeding and 10 cases of grade 4 bleeding. There were 102 cases of non-serious bleeding, including 30 cases of grade 0, 24 cases of grade 1 bleeding, and 48 cases of grade 2 bleeding. The proportion of serum promyelocytes, white blood cell count, and D-D level in the severe bleeding group were significantly higher than those in the non severe bleeding group (P < 0.05), while the levels of PLT and FIB were significantly lower than those in the non-serious bleeding group (P < 0.05). The serum Ficolin-3 levels in the severe bleeding group were significantly lower than those in the non severe bleeding group before treatment, days of treatment, 14 days of treatment, and 30 days of treatment (P < 0.05). Confirmed by point two column correlation, serum Ficolin-3 levels were negatively correlated with early severe bleeding in newly diagnosed APL patients before treatment, 7 days, 14 days, and 30 days after treatment (r values were -0.485, -0.397, -0.304, and -0.183, respectively). The receiver operating characteristic curve (ROC) graph of the subjects was drawn, and the results showed that the area under the curve (AUC) of serum Ficolin-3 levels before treatment and at 7 and 14 days after treatment for predicting early severe bleeding in newly diagnosed APL patients was greater than 0.7, all of which had certain predictive efficacy, and the serum Ficolin-3 level before treatment had the best predictive efficacy. CONCLUSION: The serum Ficolin-3 levels in newly diagnosed APL patients are associated with early severe bleeding, and the serum Ficolin-3 levels before treatment have a significant advantage in predicting early severe bleeding in newly diagnosed APL patients.
Assuntos
Hemorragia , Leucemia Promielocítica Aguda , Humanos , Leucemia Promielocítica Aguda/complicações , Leucemia Promielocítica Aguda/sangue , Hemorragia/etiologia , Feminino , Masculino , Fibronectinas/sangue , Lectinas/sangue , Adulto , Tretinoína , Glicoproteínas/sangueRESUMO
The present study described an extremely rare case of acute promyelocytic leukemia (APL) characterized by a complex threeway (15;22;17)(q22;q11.2;q21) translocation. Acute promyelocytic leukemia (APL) is a specific subtype of acute myeloid leukemia with distinctive clinical and therapeutic characteristics. Besides being characterized by the t(15;17)(q22;q12) translocation, this subtype is also notable for its response to all-trans-retinoic acid (ATRA) treatment. APL is highly responsive to a combination of ATRA and chemotherapeutic agents, achieving over 90 % complete remission rates and over 80 % long-term remission rates. In this case, a 79-year-old male patient presented with complaints of weakness, fatigue, and petechial rash, with no other significant medical history except for diabetes mellitus and hypertension. Conventional cytogenetic methods, dual-color dual-fusion, and dual-color break-apart fluorescent in situ hybridization techniques together identified the t(15;22;17) translocation. RT-PCR analysis was performed for expression of PML/RARA fusion transcripts. The patient, diagnosed with APL, exhibited a complete response to all-trans retinoic acid (ATRA) and idarubicin treatment. In this paper, we present the second documented case of t(15;22;17) and explore the remarkable remission observed following treatment with All-Trans Retinoic Acid (ATRA).
Assuntos
Cromossomos Humanos Par 17 , Leucemia Promielocítica Aguda , Translocação Genética , Humanos , Masculino , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/tratamento farmacológico , Idoso , Cromossomos Humanos Par 17/genética , Tretinoína/uso terapêutico , Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 22/genética , Hibridização in Situ FluorescenteRESUMO
This study was conducted to identify the characteristics and risk factors for early death in critically ill acute promyelocytic leukaemia (APL) patients in the Hemato-oncology ICU (HICU). A total of 44 APL patients from 2017 to 2023 were included. The mortality among APL patients in the HICU was high (27/44, 61.36%). Compared with patients who survived, nonsurvivors had a longer prothrombin time (P = 0.002), lower fibrinogen (P = 0.022), higher white blood cell count (P = 0.004) and higher creatinine (P = 0.037) on hosipital admission. Severe bleeding was the most frequent complication (34 cases, 77.27%), which occurred either preinduction or on Day 5 (IQR 3-7.5 days) of induction. Cerebral bleeding associated with consciousness disturbance was the main reason for HICU admission (18 cases, 40.9%). The leading cause of death was fatal haemorrhage (18/34, 52.94%), which occurred either preinduction or on Day 4 (IQR 3-7 days) of induction. Another common cause of death was sepsis (8/18, 44.44%), which occurred on Day 12 (IQR 9.5-24.75 days) during induction. In conclusion, the main cause of death in APL patients treated in the HICU was primary being attributed to fatal bleeding, followed by sepsis.
Assuntos
Estado Terminal , Unidades de Terapia Intensiva , Leucemia Promielocítica Aguda , Humanos , Leucemia Promielocítica Aguda/mortalidade , Leucemia Promielocítica Aguda/complicações , Feminino , Masculino , Estado Terminal/mortalidade , Pessoa de Meia-Idade , Adulto , Fatores de Risco , Idoso , Hemorragia/mortalidade , Mortalidade Hospitalar , Estudos Retrospectivos , Sepse/mortalidade , Sepse/complicaçõesRESUMO
ABSTRACT: Atypical acute promyelocytic leukemia (aAPL) presents a complex landscape of retinoic acid receptor (RAR) fusion genes beyond the well-known PML::RARA fusion. Among these, 31 individually rare RARA and RARG fusion genes have been documented, often reported in the canonical X::RAR bipartite fusion form. Intriguingly, some artificially mimicked bipartite X::RAR fusions respond well to all-trans retinoic acid (ATRA) in vitro, contrasting with the ATRA resistance observed in patients. To unravel the underlying mechanisms, we conducted a comprehensive molecular investigation into the fusion transcripts in 27 RARA fusion gene-positive aAPL (RARA-aAPL) and 21 RARG-aAPL cases. Our analysis revealed an unexpected novel form of X::RAR::X- or X::RAR::Y-type tripartite fusions in certain RARA-aAPL and all RARG-aAPL cases, with shared features and notable differences between these 2 disease subgroups. In RARA-aAPL cases, the occurrence of RARA 3' splices was associated with their 5' fusion partner genes, mapping across the coding region of helix 11_12 (H11_12) within the ligand-binding domain (LBD), resulting in LBD-H12 or H11_12 truncation. In RARG-aAPL cases, RARG 3' splices were consistently localized to the terminus of exon 9, leading to LBD-H11_12 truncation. Significant differences were also observed between RARA and RARG 5' splice patterns. Our analysis also revealed extensive involvement of transposable elements in constructing RARA and RARG 3' fusions, suggesting transposition mechanisms for fusion gene ontogeny. Both protein structural analysis and experimental results highlighted the pivotal role of LBD-H11_12/H12 truncation in driving ATRA unresponsiveness and leukemogenesis in tripartite fusion-positive aAPL, through a protein allosteric dysfunction mechanism.
Assuntos
Leucemia Promielocítica Aguda , Proteínas de Fusão Oncogênica , Receptor alfa de Ácido Retinoico , Receptor gama de Ácido Retinoico , Humanos , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patologia , Receptor alfa de Ácido Retinoico/genética , Receptor alfa de Ácido Retinoico/metabolismo , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Receptores do Ácido Retinoico/genética , Receptores do Ácido Retinoico/metabolismo , Masculino , Tretinoína/metabolismo , FemininoRESUMO
Acute promyelocytic leukemia (APL) is an uncommon subtype of acute myelogenous leukemia (AML) that was previously one of the most fatal forms of acute leukemia. With advances in diagnosis and treatment, APL has become one of the most curable myeloid leukemias. The major reason for treatment failure in APL is early death after initiation of treatment. We performed a retrospective cross-sectional analysis of the Healthcare Cost and Utilization Project 2016 and 2019 Kids' Inpatient Database, with the diagnosis of APL or AML not in remission as defined by ICD-10-CM codes. We compared complications and outcomes associated with APL and AML (exclusive of APL) in hospitalized children in the U.S. and described yearly national incidence. The national incidence of APL was 2.2 cases per million children per year. Children with APL were more likely to have cardiopulmonary complications (OR 1.79; CI 1.20-2.67; p = 0.004), coagulation abnormalities or DIC (OR 7.75; CI 5.81-10.34; p < 0.001), pulmonary hemorrhage (OR 2.18; CI 1.49-3.17; p < 0.001), and intracranial hemorrhage (OR 10.82; CI 5.90-19.85; p < 0.001) and less likely to have infectious complications (OR 0.48; CI 0.34-0.67; p < 0.001) compared to children with AML. In-hospital mortality rates were similar in children with APL and AML (4.2% vs 2.6%; OR 1.62; CI 0.86-3.06; p = 0.13), while the median length of stay for children who died from APL was shorter compared to AML (2 (IQR: 1-7) versus 25 (IQR: 5-66) days; p < 0.05). Hemorrhagic complications occur more often, and infectious complications occur less often in hospitalized children with APL compared to AML.
Assuntos
Bases de Dados Factuais , Leucemia Promielocítica Aguda , Humanos , Criança , Leucemia Promielocítica Aguda/mortalidade , Leucemia Promielocítica Aguda/epidemiologia , Leucemia Promielocítica Aguda/complicações , Feminino , Masculino , Pré-Escolar , Estudos Retrospectivos , Adolescente , Lactente , Estudos Transversais , Estados Unidos/epidemiologia , IncidênciaRESUMO
The transformation of acute promyelocytic leukemia (APL) from the most fatal to the most curable subtype of acute myeloid leukemia (AML), with long-term survival exceeding 90%, has represented one of the most exciting successes in hematology and in oncology. APL is a paradigm for oncoprotein-targeted cure.APL is caused by a 15/17 chromosomal translocation which generates the PML-RARA fusion protein and can be cured by the chemotherapy-free approach based on the combination of two therapies targeting PML-RARA: retinoic acid (RA) and arsenic. PML-RARA is the key driver of APL and acts by deregulating transcriptional control, particularly RAR targets involved in self-renewal or myeloid differentiation, also disrupting PML nuclear bodies. PML-RARA mainly acts as a modulator of the expression of specific target genes: genes whose regulatory elements recruit PML-RARA are not uniformly repressed but also may be upregulated or remain unchanged. RA and arsenic trioxide directly target PML-RARA-mediated transcriptional deregulation and protein stability, removing the differentiation block at promyelocytic stage and inducing clinical remission of APL patients.
Assuntos
Leucemia Promielocítica Aguda , Proteínas de Fusão Oncogênica , Tretinoína , Humanos , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patologia , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Tretinoína/uso terapêutico , Tretinoína/farmacologia , Trióxido de Arsênio/uso terapêutico , Trióxido de Arsênio/farmacologia , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Arsenicais/uso terapêutico , Arsenicais/farmacologia , Óxidos/uso terapêutico , Óxidos/farmacologia , AnimaisRESUMO
ABSTRACT: Fusion oncogenes can be cancer-defining molecular alterations that are essential for diagnosis and therapy selection.1,2 Rapid and accessible molecular diagnostics for fusion-driven leukemias such as acute promyelocytic leukemia (APL), Philadelphia chromosome-positive acute lymphoblastic leukemia, and chronic myeloid leukemia (CML) are unavailable, creating a barrier to timely diagnosis and effective targeted therapy in many health care settings, including community hospitals and low-resource environments. We developed CRISPR-based RNA-fusion transcript detection assays using SHERLOCK (specific high-sensitivity enzymatic reporter unlocking) for the diagnosis of fusion-driven leukemias. We validated these assays using diagnostic samples from patients with APL and CML from academic centers and dried blood spots from low-resource environments, demonstrating 100% sensitivity and specificity. We identified assay optimizations to enable the use of these tests outside of tertiary cancer centers and clinical laboratories, enhancing the potential impact of this technology. Rapid point-of-care diagnostics can improve outcomes for patients with cancer by expanding access to therapies for highly treatable diseases that would otherwise lead to serious adverse outcomes due to delayed or missed diagnoses.