RESUMEN
BACKGROUND: Blast transformation is a rare but well-recognized event in Philadelphia-negative myeloproliferative neoplasms associated with a poor prognosis. Secondary acute myeloid leukemias evolving from myeloproliferative neoplasms are characterized by a unique set of cytogenetic and molecular features distinct from de novo disease. t(8;21) (q22;q22.1); RUNX1::RUNX1T1, one of the most frequent cytogenetic abnormalities in de novo acute myeloid leukemia, is rarely observed in post-myeloproliferative neoplasm acute myeloid leukemia. Here we report a case of secondary acute myeloid leukemia with t(8;21) evolving from JAK2-mutated essential thrombocythemia. CASE PRESENTATION: The patient was a 74-year-old Japanese woman who was referred because of thrombocytosis (platelets 1046 × 109/L). Bone marrow was hypercellular with increase of megakaryocytes. Chromosomal analysis presented normal karyotype and genetic test revealed JAK2 V617F mutation. She was diagnosed with essential thrombocythemia. Thrombocytosis had been well controlled by oral administration of hydroxyurea; 2 years after the initial diagnosis with ET, she presented with leukocytosis (white blood cells 14.0 × 109/L with 82% of blasts), anemia (hemoglobin 91 g/L), and thrombocytopenia (platelets 24 × 109/L). Bone marrow was hypercellular and filled with 80% of myeloperoxidase-positive blasts bearing Auer rods. Chromosomal analysis revealed t(8;21) (q22;q22.1) and flow cytometry presented positivity of CD 13, 19, 34, and 56. Molecular analysis showed the coexistence of RUNX1::RUNX1T1 chimeric transcript and heterozygous JAK2 V617F mutation in leukemic blasts. She was diagnosed with secondary acute myeloid leukemia with t(8;21)(q22;q22.1); RUNX1::RUNX1T1 evolving from essential thrombocythemia. She was treated with combination chemotherapy with venetoclax and azacytidine. After the first cycle of the therapy, blasts disappeared from peripheral blood and decreased to 1.4% in bone marrow. After the chemotherapy, RUNX1::RUNX1T1 chimeric transcript disappeared, whereas mutation of JAK2 V617F was still present in peripheral leukocytes. CONCLUSIONS: To our best knowledge, the present case is the first one with JAK2 mutation preceding the acquisition of t(8;21). Our result suggests that t(8;21); RUNX1::RUNX1T1 can be generated as a late event in the progression of JAK2-mutated myeloproliferative neoplasms. The case presented typical morphological and immunophenotypic features associated with t(8;21) acute myeloid leukemia.
Asunto(s)
Subunidad alfa 2 del Factor de Unión al Sitio Principal , Janus Quinasa 2 , Leucemia Mieloide Aguda , Trombocitemia Esencial , Translocación Genética , Humanos , Femenino , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Anciano , Janus Quinasa 2/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Trombocitemia Esencial/genética , Trombocitemia Esencial/tratamiento farmacológico , Proteína 1 Compañera de Translocación de RUNX1/genética , Cromosomas Humanos Par 8/genética , Cromosomas Humanos Par 21/genética , MutaciónRESUMEN
RUNX1::RUNX1T1 (R::RT1) acute myeloid leukaemia (AML) remains a clinical challenge, and further research is required to model and understand leukaemogenesis. Previous zebrafish R::RT1 models were hampered by embryonic lethality and low penetrance of the malignant phenotype. Here, we overcome this by developing an adult zebrafish model in which the human R::RT1 isoform 9a is co-expressed with the frequently co-occurring oncogenic NRASG12D mutation in haematopoietic stem and progenitor cells (HSPCs), using the Runx1+23 enhancer. Approximately 50% of F0 9a+NRASG12D transgenic zebrafish developed signs of haematological disease between 5 and 14â months, with 27% exhibiting AML-like pathology: myeloid precursor expansion, erythrocyte reduction, kidney marrow hypercellularity and the presence of blasts. Moreover, only 9a+NRASG12D transplant recipients developed leukaemia with high rates of mortality within 40â days, inferring the presence of leukaemia stem cells. These leukaemic features were rare or not observed in animals expressing either the NRAS or 9a oncogenes alone, suggesting 9a and NRAS cooperation drives leukaemogenesis. This novel adult AML zebrafish model provides a powerful new tool for investigating the basis of R::RT1 - NRAS cooperativity with the potential to uncover new therapeutic targets.
Asunto(s)
Animales Modificados Genéticamente , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Modelos Animales de Enfermedad , Mutación , Isoformas de Proteínas , Pez Cebra , Animales , Humanos , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , GTP Fosfohidrolasas/genética , GTP Fosfohidrolasas/metabolismo , Células Madre Hematopoyéticas/metabolismo , Leucemia Mieloide/genética , Leucemia Mieloide/etiología , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/etiología , Oncogenes , Isoformas de Proteínas/genética , Proteína 1 Compañera de Translocación de RUNX1/genética , Proteína 1 Compañera de Translocación de RUNX1/metabolismo , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismoRESUMEN
PURPOSE: T(8;21)(q22;q22.1)/AML1-ETO positive acute myeloid leukemia (AE-AML) is sensitive to conventional chemotherapy with a favorable prognosis. However, recent small case reports suggest the limited effectiveness of venetoclax (VEN) and hypomethylating agents (HMA) in treating AE-AML. The aim of this retrospective study was to evaluate the effectiveness of VEN plus AZA (VA) in AE-AML and explore whether adding homoharringtonine (HHT) to VA (VAH) could improve the response. METHODS: Patients who received VEN plus AZA and HHT (VAH) or VEN plus AZA (VA) regimens were included in this retrospective study. The endpoints of this study were to evaluate the rate of composite complete remission (CRc), measurable residual disease (MRD), event-free survival (EFS), overall survival (OS), and relapse between VAH and VA groups. RESULTS: A total of 32 AE-AML patients who underwent VA or VAH treatments (newly diagnosed with VA, ND-VA, n = 8; relapsed/refractory with VA, R/R-VA, n = 10; relapsed/refractory with VAH, R/R-VAH, n = 14) were included. The CR (complete remission) /CRi (CR with incomplete count recovery) rate of ND-VA, R/R-VA and R/R-VAH were 25%, 10%, and 64.3%, respectively. Measurable residual disease (MRD) negative was observed in 66.7% of R/R-VAH and none of VA-R/R patients. Co-occurring methylation mutations are associated with poor outcomes with VA but exhibit a more favorable response with VAH treatment. Additionally, patients with c-kit mutation presented inferior outcomes with both VEN-based regimens. All regimens were tolerated well by all patients. CONCLUSION: Our data confirmed the poor response of VA in AE-AML, whether used as frontline or salvage therapy. Adding HHT to VA may improve outcomes and enhance the efficacy of VEN in this population.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Azacitidina , Compuestos Bicíclicos Heterocíclicos con Puentes , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Homoharringtonina , Leucemia Mieloide Aguda , Proteína 1 Compañera de Translocación de RUNX1 , Sulfonamidas , Humanos , Homoharringtonina/administración & dosificación , Homoharringtonina/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Femenino , Estudios Retrospectivos , Azacitidina/administración & dosificación , Sulfonamidas/administración & dosificación , Anciano , Adulto , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Proteína 1 Compañera de Translocación de RUNX1/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proteínas de Fusión Oncogénica/genética , Adulto JovenAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Leucemia Mieloide Aguda , Ftalazinas , Piperazinas , Proteína 1 Compañera de Translocación de RUNX1 , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Piperazinas/administración & dosificación , Piperazinas/uso terapéutico , Ftalazinas/administración & dosificación , Ftalazinas/uso terapéutico , Proteína 1 Compañera de Translocación de RUNX1/genética , Anciano , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Proteínas de Fusión Oncogénica/genética , Resultado del Tratamiento , Masculino , Femenino , Recurrencia , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patologíaRESUMEN
Systemic mastocytosis (SM) with RUNX1-RUNX1T1 positive acute myeloid leukemia (AML) is a rare myeloid tumor with no standard treatment. Two cases of SM patients with RUNX1-RUNX1T1 positive AML treated with sequential avapritinib after allogeneic hematopoietic stem cell transplantation (allo-HSCT) were reported in Henan Cancer Hospital. Mast cell in bone marrow disappeared, C-KIT mutation and RUNX1-RUNX1T1 fusion gene remained negative. Allo-HSCT sequential avapritinib is an effective treatment for SM patients with RUNX1-RUNX1T1 positive AML.
Asunto(s)
Subunidad alfa 2 del Factor de Unión al Sitio Principal , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Mastocitosis Sistémica , Humanos , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/genética , Mastocitosis Sistémica/genética , Mastocitosis Sistémica/terapia , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Masculino , Femenino , Adulto , Proteína 1 Compañera de Translocación de RUNX1/genética , Proteínas de Fusión Oncogénica/genética , Persona de Mediana Edad , Trasplante Homólogo , Pirazinas/administración & dosificación , Pirazoles , Pirroles , TriazinasRESUMEN
Disease recurrence is the leading cause of treatment failure in patients with RUNX1::RUNXT1-positive acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Post-transplant maintenance therapy, guided by monitoring minimal residual disease (MRD), is commonly administered; however, relapse rates remain high. This prospective study aimed to assess the effectiveness and safety of epigenetic agents as prophylactic therapy in patients with RUNX1::RUNXT1-positive AML. Thirty high-risk patients received prophylactic therapy (n = 17 and n = 13 in the chidamide and AZA groups, respectively) between January 2019 and July 2023. 34 high-risk patients who received preemptive treatment due to molecular relapse were included in the analysis. The two-year relapse-free survival (RFS) and overall survival (OS) were significantly higher in the prophylactic group compared to the preemptive group (82.82% vs. 51.38%, P = 0.014; 86.42% vs. 56.16%, P = 0.025, respectively); 2-year cumulative incidence of relapse rates were 13.8% and 36.40%, respectively (P = 0.037). In conclusion, prophylactic therapy with epigenetic agents may improve long-term prognosis and is well-tolerated in patients with RUNX1::RUNXT1-positive high-risk AML. Timely post-transplant prophylactic therapy may be more effective than preemptive therapy based on positive MRD results.
Asunto(s)
Subunidad alfa 2 del Factor de Unión al Sitio Principal , Epigénesis Genética , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Femenino , Masculino , Persona de Mediana Edad , Adulto , Epigénesis Genética/efectos de los fármacos , Estudios Prospectivos , Proteína 1 Compañera de Translocación de RUNX1/genética , Benzamidas/uso terapéutico , Neoplasia Residual , Adulto Joven , Adolescente , Aloinjertos , Azacitidina/uso terapéutico , AminopiridinasRESUMEN
OBJECTIVE: To analyze the factors affecting overall survival (OS) of adult patients with core-binding factor acute myeloid leukemia (CBF-AML) and establish a prediction model. METHODS: A total of 216 newly diagnosed patients with CBF-AML in the First Affiliated Hospital of Zhengzhou University from May 2015 to July 2021 were retrospectively analyzed. The 216 CBF-AML patients were divided into the training and the validation cohort at 7â¶3 ratio. The Cox regression model was used to analyze the clinical factors affecting OS. Stepwise regression was used to establish the optimal model and the nomogram. Receiver operating characteristic (ROC) curve, calibration curve and decision curve analysis (DCA) were used to evaluate the model performance. RESULTS: Age(≥55 years old), peripheral blood blast(≥80%), fusion gene (AML1-ETO), KIT mutations were identified as independent adverse factors for OS. The area under the ROC curve at 3-year was 0.772 and 0.722 in the training cohort and validation cohort, respectively. The predicted value of the calibration curve is in good agreement with the measured value. DCA shows that this model performs better than a single factor. CONCLUSION: This prediction model is simple and feasible, and can effectively predict the OS of CBF-AML, and provide a basis for treatment decision.
Asunto(s)
Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/diagnóstico , Pronóstico , Estudios Retrospectivos , Persona de Mediana Edad , Femenino , Masculino , Mutación , Curva ROC , Factores de Unión al Sitio Principal/genética , Nomogramas , Adulto , Proteína 1 Compañera de Translocación de RUNX1/genética , Proteínas Proto-Oncogénicas c-kit/genética , Modelos de Riesgos Proporcionales , Proteínas de Fusión Oncogénica/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genéticaRESUMEN
Acute myeloid leukemia (AML) is a malignant hematological tumor disease. Chromosomal abnormality is an independent prognostic factor in AML. AML with t(8:21) (q22; q22)/AML1-ETO (AE) is an independent disease group. In this research, a new method based on Raman spectroscopy is reported for label-free single-cell identification and analysis of AE fusion genes in clinical AML patients. Raman spectroscopy reflects the intrinsic vibration information of molecules in a label-free and non-destructive manner, and the fingerprint Raman spectrum of cells characterizes intracellular molecular types and relative concentration information, so as to realize the identification and molecular metabolism analysis of different kinds of cells. We collected the Raman spectra of bone marrow cells from clinically diagnosed AML M2 patients with and without the AE fusion gene. Through comparison of the average spectra and identification analysis based on multivariate statistical methods such as principal component analysis and linear discriminant analysis, the distinction between AE positive and negative sample cells in M2 AML patients was successfully achieved, and the single-cell identification accuracy was more than 90%. At the same time, the Raman spectra of the two types of cells were analyzed by the multivariate curve resolution alternating least squares decomposition method. It was found that the presence of the AE fusion gene may lead to the metabolic changes of lipid and nucleic acid in AML cells, which was consistent with the results of genomic and metabolomic multi-omics studies. The above results indicate that single-cell Raman spectroscopy has the potential for early identification of AE-positive AML.
Asunto(s)
Subunidad alfa 2 del Factor de Unión al Sitio Principal , Leucemia Mieloide Aguda , Proteínas de Fusión Oncogénica , Proteína 1 Compañera de Translocación de RUNX1 , Análisis de la Célula Individual , Espectrometría Raman , Humanos , Espectrometría Raman/métodos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Proteína 1 Compañera de Translocación de RUNX1/genética , Proteína 1 Compañera de Translocación de RUNX1/metabolismo , Análisis de la Célula Individual/métodos , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/análisis , Análisis de Componente Principal , Masculino , Femenino , Adulto , Persona de Mediana EdadRESUMEN
Acute myeloid leukemia (AML) is frequently linked to genetic abnormalities, with the t (8; 21) translocation, resulting in the production of a fusion oncoprotein AML1-ETO (AE), being a prevalent occurrence. This protein plays a pivotal role in t (8; 21) AML's onset, advancement, and recurrence, making it a therapeutic target. However, the development of drug molecules targeting AML1-ETO are markedly insufficient, especially used in clinical treatment. In this study, it was uncovered that Neratinib could significantly downregulate AML1-ETO protein level, subsequently promoting differentiation of t (8; 21) AML cells. Based on "differentiated active" probes, Neratinib was identified as a functional inhibitor against HNRNPA3 through covalent binding. The further studies demonstrated that HNRNPA3 function as a putative m6A reader responsible for recognizing and regulating the alternative splicing of AML-ETO pre-mRNA. These findings not only contribute to a novel insight to the mechanism governing post-transcriptional modification of AML1-ETO transcript, but also suggest that Neratinib would be promising therapeutic potential for t (8; 21) AML treatment.
Asunto(s)
Diferenciación Celular , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Leucemia Mieloide Aguda , Proteínas de Fusión Oncogénica , Quinolinas , Proteína 1 Compañera de Translocación de RUNX1 , Humanos , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Quinolinas/farmacología , Diferenciación Celular/efectos de los fármacos , Proteína 1 Compañera de Translocación de RUNX1/genética , Proteína 1 Compañera de Translocación de RUNX1/metabolismo , Precursores del ARN/metabolismo , Precursores del ARN/genética , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/metabolismo , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/genética , Translocación Genética/efectos de los fármacos , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/farmacología , Empalme Alternativo/efectos de los fármacos , Línea Celular Tumoral , Animales , RatonesRESUMEN
ABSTRACT: Molecular measurable residual disease can persist in core-binding factor acute myeloid leukemia in otherwise disease-free patients. Utilizing cell sorting followed by fluorescent in situ hybridization, we show that detection is due to mast cells.
Asunto(s)
Citometría de Flujo , Leucemia Mieloide Aguda , Mastocitos , Neoplasia Residual , Proteínas de Fusión Oncogénica , Humanos , Mastocitos/metabolismo , Mastocitos/patología , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/diagnóstico , Citometría de Flujo/métodos , Neoplasia Residual/diagnóstico , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Hibridación Fluorescente in Situ , Proteína 1 Compañera de Translocación de RUNX1/genética , Proteína 1 Compañera de Translocación de RUNX1/metabolismo , Masculino , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , FemeninoAsunto(s)
Cromosomas Humanos Par 14 , Cromosomas Humanos Par 21 , Cromosomas Humanos Par 8 , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Leucemia Mieloide Aguda , Proteína 1 Compañera de Translocación de RUNX1 , Translocación Genética , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/diagnóstico , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Proteína 1 Compañera de Translocación de RUNX1/genética , Cromosomas Humanos Par 21/genética , Cromosomas Humanos Par 8/genética , Cromosomas Humanos Par 14/genética , Proteínas de Fusión Oncogénica/genética , Cromosomas Humanos Par 15/genética , MasculinoRESUMEN
Chromosomal translocation serves as a crucial diagnostic marker in the classification of acute myeloid leukemia. Among the most prevalent cytogenetic abnormalities is t(8;21)(q22;q22), typically associated with the FAB subtype AML-M2. On occasion, alternative forms of t(8;21) have been observed. This report presents a case of AML with RUNX1::RUNX1T1, wherein the karyotype revealed t(2;2;21;8)(p21;q37;q22;q22), representing the first instance of a variant t(8;21) involving both chromosomes 2. The combination of routine karyotype analysis and fluorescence in situ hybridization proves to be an effective method for identifying complex translocations of t(8;21).
Asunto(s)
Cromosomas Humanos Par 21 , Cromosomas Humanos Par 8 , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Leucemia Mieloide Aguda , Translocación Genética , Humanos , Leucemia Mieloide Aguda/genética , Cromosomas Humanos Par 21/genética , Cromosomas Humanos Par 8/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Hibridación Fluorescente in Situ , Masculino , Cromosomas Humanos Par 2/genética , Proteína 1 Compañera de Translocación de RUNX1/genética , Cariotipificación , Femenino , Adulto , Proteínas de Fusión Oncogénica/genéticaRESUMEN
MGA (Max-gene associated) is a dual-specificity transcription factor that negatively regulates MYC-target genes to inhibit proliferation and promote differentiation. Loss-of-function mutations in MGA have been commonly identified in several hematological neoplasms, including acute myeloid leukemia (AML) with RUNX1::RUNX1T1, however, very little is known about the impact of these MGA alterations on normal hematopoiesis or disease progression. We show that representative MGA mutations identified in patient samples abolish protein-protein interactions and transcriptional activity. Using a series of human and mouse model systems, including a newly developed conditional knock-out mouse strain, we demonstrate that loss of MGA results in upregulation of MYC and E2F targets, cell cycle genes, mTOR signaling, and oxidative phosphorylation in normal hematopoietic cells, leading to enhanced proliferation. The loss of MGA induces an open chromatin state at promoters of genes involved in cell cycle and proliferation. RUNX1::RUNX1T1 expression in Mga-deficient murine hematopoietic cells leads to a more aggressive AML with a significantly shortened latency. These data show that MGA regulates multiple pro-proliferative pathways in hematopoietic cells and cooperates with the RUNX1::RUNX1T1 fusion oncoprotein to enhance leukemogenesis.
Asunto(s)
Subunidad alfa 2 del Factor de Unión al Sitio Principal , Proteínas de Unión al ADN , Leucemia Mieloide Aguda , Mutación , Proteínas Proto-Oncogénicas , Proteína 1 Compañera de Translocación de RUNX1 , Animales , Humanos , Ratones , Proliferación Celular , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Regulación Leucémica de la Expresión Génica , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Ratones Noqueados , Proteínas de Fusión Oncogénica/genética , Proteína 1 Compañera de Translocación de RUNX1/genética , Factores de Transcripción/genéticaRESUMEN
In addition to RUNX1::RUNX1T1 transcript levels, measurable residual disease monitoring using KIT mutant (KITmut ) DNA level is reportedly predictive of relapse in t (8; 21) acute myeloid leukemia (AML). However, the usefulness of KITmut transcript levels remains unknown. A total of 202 bone marrow samples collected at diagnosis and during treatment from 52 t (8; 21) AML patients with KITmut (D816V/H/Y or N822K) were tested for KITmut transcript levels using digital polymerase chain reaction. The individual optimal cutoff values of KITmut were identified by performing receiver operating characteristics curve analysis for relapse at each of the following time points: at diagnosis, after achieving complete remission (CR), and after Course 1 and 2 consolidations. The cutoff values were used to divide the patients into the KITmut -high (KIT_H) group and the KITmut -low (KIT_L) group. The KIT_H patients showed significantly lower relapse-free survival (RFS) and overall survival (OS) rates than the KIT_L patients after Course 1 consolidation (p = 0.0040 and 0.021, respectively) and Course 2 consolidation (p = 0.018 and 0.011, respectively) but not at diagnosis and CR. The <3-log reduction in the RUNX1::RUNX1T1 transcript levels after Course 2 consolidation was an independent adverse prognostic factor for RFS and OS. After Course 2 consolidation, the KIT_H patients with >3-log reduction in the RUNX1::RUNX1T1 transcript levels (11/45; 24.4%) had similar RFS as that of patients with <3-log reduction in the RUNX1::RUNX1T1 transcript levels. The combination of KITmut and RUNX1::RUNX1T1 transcript levels after Course 2 consolidation may improve risk stratification in t (8; 21) AML patient with KIT mutation.
Asunto(s)
Leucemia Mieloide Aguda , Proteínas Proto-Oncogénicas c-kit , Humanos , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/terapia , Neoplasia Residual/genética , Respuesta Patológica Completa , Pronóstico , Recurrencia , Proteína 1 Compañera de Translocación de RUNX1/genética , Translocación Genética , Proteínas Proto-Oncogénicas c-kit/genéticaRESUMEN
BACKGROUND: Acute myeloid leukemia (AML) with t(8;21)(q22;q22.1); RUNX1::RUNX1T1 has a relatively favorable prognosis with a high complete remission rate and long disease-free survival. METHODS AND RESULTS: Here we describe a patient who had AML with t(8;21)(q22;q22.1); RUNX1::RUNX1T1. Cooperating mutations including KRAS and ASXL1, and with other abnormal karyotype del(17) and with a myelomonocytic differentiation. CONCLUSIONS: The patient relapsed despite achieving a morphologic complete remission (CR).
Asunto(s)
Leucemia Mieloide Aguda , Translocación Genética , Humanos , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Proteína 1 Compañera de Translocación de RUNX1/genética , Leucemia Mieloide Aguda/genética , MutaciónRESUMEN
Erythroblastic sarcoma (ES) (previously called chloroma or granulocytic sarcoma) are rare hematological neoplams characterized by the proliferation of myeloid blasts at extramedullary sites, and primarily involve the skin and soft tissue of middle-aged adults. ES may be concomitant with or secondary to myeloid neoplasms (mostly acute myeloid leukemia (AML)) or in isolated cases (de novo) without infiltration of the bone marrow by blasts. ES share cytogenetic and molecular abnormalities with AML, including RUNX1T1 fusions. Some of these alterations seem to be correlated with particular sites of involvement. Herein, we report an isolated erythroblastic sarcoma with NFIA::RUNX1T1 located in the central nervous system (CNS) of a 3-year-old boy. Recently, two pediatric cases of CNS MS with complete molecular characterization have been documented. Like the current case, they concerned infants (2 and 3 years-old) presenting a brain tumor (pineal involvement) with leptomeningeal dissemination. Both cases also harbored a NFIA::RUNX1T3 fusion. ES constitutes a diagnostic challenge for neuropathologists because it does not express differentiation markers such as CD45, and may express CD99 which could be confused with CNS Ewing sarcoma. CD43 is the earliest pan-hematopoietic marker and CD45 is not expressed by erythroid lineage cells. E-cadherin (also a marker of erythroid precursors) and CD117 (expressed on the surface of erythroid lineage cells) constitute other immunhistochemical hallmarks of ES. The prognosis of patients with ES is similar to that of other patients with AML but de novo forms seem to have a poorer prognosis, like the current case. To conclude, pediatric ES with NFIA::RUNX1T1/3 fusions seem to have a tropism for the CNS and thus constitute a potential pitfall for neuropathologists. Due to the absence of circulating blasts and a DNA-methylation signature, the diagnosis must currently be made by highlighting the translocation and expression of erythroid markers.
Asunto(s)
Neoplasias del Sistema Nervioso Central , Leucemia Mieloide Aguda , Sarcoma Mieloide , Sarcoma , Preescolar , Humanos , Lactante , Masculino , Persona de Mediana Edad , Médula Ósea/patología , Neoplasias del Sistema Nervioso Central/patología , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Factores de Transcripción NFI/genética , Factores de Transcripción NFI/metabolismo , Proteína 1 Compañera de Translocación de RUNX1/metabolismo , Sarcoma/metabolismo , Sarcoma/patología , Sarcoma Mieloide/genética , Sarcoma Mieloide/diagnóstico , Sarcoma Mieloide/metabolismoRESUMEN
T(8;21)(q22;q22), which generates the AML1-ETO fusion oncoprotein, is a common chromosomal abnormality in acute myeloid leukemia (AML) patients. Despite having favorable prognosis, 40% of patients will relapse, highlighting the need for innovative models and application of the newest technologies to study t(8;21) leukemogenesis. Currently, available AML1-ETO mouse models have limited utility for studying the pre-leukemic stage because AML1-ETO produces mild hematopoietic phenotypes and no leukemic transformation. Conversely, overexpression of a truncated variant, AML1-ETO9a (AE9a), promotes fully penetrant leukemia and is too potent for studying pre-leukemic changes. To overcome these limitations, we devised a germline-transmitted Rosa26 locus AE9a knock-in mouse model that moderately overexpressed AE9a and developed leukemia with long latency and low penetrance. We observed pre-leukemic alterations in AE9a mice, including skewing of progenitors towards granulocyte/monocyte lineages and replating of stem and progenitor cells. Next, we performed single-cell RNA sequencing to identify specific cell populations that contribute to these pre-leukemic phenotypes. We discovered a subset of common myeloid progenitors that have heightened granulocyte/monocyte bias in AE9a mice. We also observed dysregulation of key hematopoietic transcription factor target gene networks, blocking cellular differentiation. Finally, we identified Sox4 activation as a potential contributor to stem cell self-renewal during the pre-leukemic stage.
Asunto(s)
Leucemia Mieloide Aguda , Preleucemia , Humanos , Ratones , Animales , Proteína 1 Compañera de Translocación de RUNX1/genética , Leucemia Mieloide Aguda/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Animales Modificados Genéticamente , Análisis de Secuencia de ARN , Proteínas de Fusión Oncogénica/genéticaRESUMEN
BACKGROUND: Pediatric core binding factor acute myeloid leukemia (CBF-AML), although considered a favorable risk subtype, exhibits variable outcomes primarily driven by additional genetic abnormalities, such as KIT mutations. PROCEDURE: In this study, we examined the prognostic impact of KIT mutations in 130 pediatric patients with CBF-AML, treated uniformly at a single center over 4 years (2017-2021). KIT mutations were detected via next-generation sequencing using a myeloid panel comprising 52 genes for most patients. RESULTS: Our findings revealed that KIT mutations were present in 31% of CBF-AML cases. Exon 17 KIT mutation was most commonly (72%) seen with notable occurrences at the D816 and N822 residue in 48% and 39% of cases, respectively. The 3-year cumulative incidence of relapse (CIR) and overall survival (OS) for patients with exon 17 KIT mutation were 36% and 40%, respectively, and was significantly worse in comparison to other site KIT mutations (3-year CIR: 11%; OS: 64%) and without KIT mutation (3-year CIR: 13%; OS:71%). Notably, the prognostic impact of KIT mutations was prominent in patients with RUNX1::RUNX1T1, but not in those with CBFB::MYH11 fusion. Additionally, a high KIT variant-allele frequency (VAF) (>33%) predicted for a higher disease relapse; 3-year CIR of 40% for VAF greater than 33% versus 7% for VAF less than 33%. When adjusted for site of KIT mutation and end-of-induction measurable residual disease, VAF greater than 33% correlated with poor OS (hazard ratio [HR]: 4.4 [95% CI: 1.2-17.2], p = .034). CONCLUSION: Exon 17 KIT mutations serve as an important predictor of relapse in RUNX1::RUNX1T1 pediatric AML. In addition, a high KIT VAF may predict poor outcomes in these patients. These results emphasize the need to incorporate KIT mutational analysis into risk stratification for pediatric CBF-AML.
Asunto(s)
Subunidad alfa 2 del Factor de Unión al Sitio Principal , Leucemia Mieloide Aguda , Humanos , Niño , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Proteínas Proto-Oncogénicas c-kit/genética , Leucemia Mieloide Aguda/terapia , Mutación , Pronóstico , Exones/genética , Recurrencia , Proteína 1 Compañera de Translocación de RUNX1/genéticaRESUMEN
Understanding the molecular pathogenesis of acute myeloid leukemia (AML) with well-defined genomic abnormalities has facilitated the development of targeted therapeutics. Patients with t(8;21) AML frequently harbor a fusion gene RUNX1-RUNX1T1 and KIT mutations as "secondary hit", making the disease one of the ideal models for exploring targeted treatment options in AML. In this study we investigated the combination therapy of agents targeting RUNX1-RUNX1T1 and KIT in the treatment of t(8;21) AML with KIT mutations. We showed that the combination of eriocalyxin B (EriB) and homoharringtonine (HHT) exerted synergistic therapeutic effects by dual inhibition of RUNX1-RUNX1T1 and KIT proteins in Kasumi-1 and SKNO-1 cells in vitro. In Kasumi-1 cells, the combination of EriB and HHT could perturb the RUNX1-RUNX1T1-responsible transcriptional network by destabilizing RUNX1-RUNX1T1 transcription factor complex (AETFC), forcing RUNX1-RUNX1T1 leaving from the chromatin, triggering cell cycle arrest and apoptosis. Meanwhile, EriB combined with HHT activated JNK signaling, resulting in the eventual degradation of RUNX1-RUNX1T1 by caspase-3. In addition, HHT and EriB inhibited NF-κB pathway through blocking p65 nuclear translocation in two different manners, to synergistically interfere with the transcription of KIT. In mice co-expressing RUNX1-RUNX1T1 and KITN822K, co-administration of EriB and HHT significantly prolonged survival of the mice by targeting CD34+CD38- leukemic cells. The synergistic effects of the two drugs were also observed in bone marrow mononuclear cells (BMMCs) of t(8;21) AML patients. Collectively, this study reveals the synergistic mechanism of the combination regimen of EriB and HHT in t(8;21) AML, providing new insight into optimizing targeted treatment of AML.