RESUMEN
Drug resistance in chronic myeloid leukaemia (CML) may occur via mutations in the causative BCR::ABL1 fusion or BCR::ABL1-independent mechanisms. We analysed 48 patients with BCR::ABL1-independent resistance for the presence of secondary fusion genes by RNA sequencing. We identified 10 of the most frequently detected secondary fusions in 21 patients. Validation studies, cell line models, gene expression analysis and drug screening revealed differences with respect to proliferation rate, differentiation and drug sensitivity. Notably, expression of RUNX1::MECOM led to resistance to ABL1 tyrosine kinase inhibitors in vitro. These results suggest secondary fusions contribute to BCR::ABL1-independent resistance and may be amenable to combined therapies.
Asunto(s)
Proteínas de Fusión bcr-abl , Leucemia Mielógena Crónica BCR-ABL Positiva , Humanos , Proteínas de Fusión bcr-abl/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Mutación , Línea Celular , Resistencia a Antineoplásicos/genéticaRESUMEN
8p11 myeloproliferative syndrome (EMS) represents a unique World Health Organization (WHO)-classified hematologic malignancy defined by translocations of the FGFR1 receptor. The syndrome is a myeloproliferative neoplasm characterized by eosinophilia and lymphadenopathy, with risk of progression to either acute myeloid leukemia (AML) or T- or B-lymphoblastic lymphoma/leukemia. Within the EMS subtype, translocations between breakpoint cluster region (BCR) and fibroblast growth factor receptor 1 (FGFR1) have been shown to produce a dominant fusion protein that is notoriously resistant to tyrosine kinase inhibitors (TKIs). Here, we report two cases of BCR-FGFR1+ EMS identified via RNA sequencing (RNA-seq) and confirmed by fluorescence in situ hybridization (FISH). Sanger sequencing revealed that both cases harbored the exact same breakpoint. In the first case, the patient presented with AML-like disease, and in the second, the patient progressed to B-cell acute lymphoblastic leukemia (B-ALL). Additionally, we observed that that primary leukemia cells from Case 1 demonstrated sensitivity to the tyrosine kinase inhibitors ponatinib and dovitinib that can target FGFR1 kinase activity, whereas primary cells from Case 2 were resistant to both drugs. Taken together, these results suggest that some but not all BCR-FGFR1 fusion positive leukemias may respond to TKIs that target FGFR1 kinase activity.
Asunto(s)
Leucemia/diagnóstico , Leucemia/genética , Proteínas de Fusión Oncogénica/genética , Proteínas Proto-Oncogénicas c-bcr/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Biomarcadores de Tumor , Biopsia , Terapia Combinada/efectos adversos , Terapia Combinada/métodos , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Resultado Fatal , Femenino , Humanos , Hibridación Fluorescente in Situ , Cariotipo , Leucemia/terapia , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-bcr/metabolismo , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Análisis de Secuencia de ADN , Translocación Genética , Resultado del TratamientoRESUMEN
The effect of different leaving groups on the substitution versus elimination outcomes with C-5 d-glucose derivatives was investigated. The stereochemical configurations of 3-O-benzyl-1,2-O-iso-propyl-idene-5-O-methane-sulfonyl-6-O-tri-phenyl-methyl-α-d-gluco-furan-ose, C36H38O8S (3) [systematic name: 1-[(3aR,5R,6S,6aR)-6-benz-yloxy-2,2-di-methyl-tetra-hydro-furo[2,3-d][1,3]dioxol-5-yl)-2-(trit-yloxy)ethyl methane-sulfonate], a stable inter-mediate, and 5-azido-3-O-benzyl-5-de-oxy-1,2-O-iso-propyl-idene-6-O-tri-phenyl-methyl-ß-l-ido-furan-ose, C35H35N3O5 (4) [systematic name: (3aR,5S,6S,6aR)-5-[1-azido-2-(trit-yloxy)eth-yl]-6-benz-yloxy-2,2-di-methyl-tetra-hydro-furo[2,3-d][1,3]dioxole], a substitution product, were examined and the inversion of configuration for the azido group on C-5 in 4 was confirmed. The absolute structures of the mol-ecules in the crystals of both compounds were confirmed by resonant scattering. In the crystal of 3, neighbouring mol-ecules are linked by C-Hâ¯O hydrogen bonds, forming chains along the b-axis direction. The chains are linked by C-Hâ¯π inter-actions, forming layers parallel to the ab plane. In the crystal of 4, mol-ecules are also linked by C-Hâ¯O hydrogen bonds, forming this time helices along the a-axis direction. The helices are linked by a number of C-Hâ¯π inter-actions, forming a supra-molecular framework.