Microambiente medular en la leucemia mieloide crónica: su relación con la enfermedad y la respuesta al tratamiento

Abstract

Bone marrow microenvironment in chronic myeloid leukemia: Implications for disease physiopathology and response to treatment a leucemia mieloide crónica (LMC) es una neoplasia mieloproliferativa cuyo origen está relacionado con la adquisición del gen de fusión BCR-ABL1, asociado a la t (9;22) (q34;q11) 1 . Representa cerca de 15-20% de los casos de las leucemias en el adulto, aparece frecuentemente hacia quinta o sexta década de la vida y su incidencia es de 1-2 casos por 100.000 habitantes por año 2,3 . La enfermedad sigue un curso progresivo, que se inicia con la fase crónica que es indolente, seguida de una trasformación de la enfermedad hacia la denominada fase acelerada y finalmente la crisis blástica, a la que se llega en todos los casos de no mediar una terapia efectiva. Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm related to the presence of the BCR-ABL1 fusion gene, linked to t (9;22) (q34;q11El tratamiento actual con inhibidores de tirosina quinasa (ITK) como el imatinib mesilato (IM) es capaz de lograr una supervivencia libre de progresión de 81% a los 8 años de acuerdo con los datos del estudio IRIS 4 . El IM ha demostrado ser útil incluso en adultos mayores con comorbilidades asociadas, logrando respuestas similares a los pacientes jóvenes en estudios observacionales 5 . Sin embargo, debe considerarse que del 45% de los pacientes que abandonaron el estudio IRIS en el período de seguimiento señalado, un tercio lo hizo por "resultados clínicos no satisfactorios", lo que sugiere que aún existe un grupo de pacientes en los cuales el mecanismo de acción del fármaco no ha logrado el objetivo terapéutico.La resistencia a la acción de los ITK puede

Arsenic Trioxide: Pharmacological Applications

“…Another disease that can be treated through ATO is chronic myeloid leukemia (CML). CML is a myeloproliferative neoplasm originated from the acquisition of the BCR-ABL fusion gene associated with t 9;22) (q34; q11) [13]. Specifically, the main cause of CML is believed to be a chromosomal abnormality in a chromosome called Philadelphia (Ph1), the result of a reciprocal translocation in a single fusion gene, called BCR-ABL, that is a mutation formed by the combination of two genes (the BCR and the ABL).…”

“…Specifically, the main cause of CML is believed to be a chromosomal abnormality in a chromosome called Philadelphia (Ph1), the result of a reciprocal translocation in a single fusion gene, called BCR-ABL, that is a mutation formed by the combination of two genes (the BCR and the ABL). [14,15] From a pathophysiological point of view, the BCR-ABL gene is distributed throughout the cytoplasm and interacts with proliferation, differentiation, and survival functions [13]. This generates interferences in the MAPK mechanisms (which causes an expansion of the tumor clone), in the PI3K pathway (which suppresses programmed cell death), and in focal adhesion components, which decreases cell adhesion, among others [13].…”

“…[14,15] From a pathophysiological point of view, the BCR-ABL gene is distributed throughout the cytoplasm and interacts with proliferation, differentiation, and survival functions [13]. This generates interferences in the MAPK mechanisms (which causes an expansion of the tumor clone), in the PI3K pathway (which suppresses programmed cell death), and in focal adhesion components, which decreases cell adhesion, among others [13]. In addition, its medullary microenvironment is characterized by factors such as the reduced capacity to support normal hematopoiesis, protection against apoptosis, and induction of resistance mediated by cytokines and cell-cell interactions [13].…”

“…This generates interferences in the MAPK mechanisms (which causes an expansion of the tumor clone), in the PI3K pathway (which suppresses programmed cell death), and in focal adhesion components, which decreases cell adhesion, among others [13]. In addition, its medullary microenvironment is characterized by factors such as the reduced capacity to support normal hematopoiesis, protection against apoptosis, and induction of resistance mediated by cytokines and cell-cell interactions [13]. Likewise, there is a vascular endothelial growth factor (VEGF) which is associated with the growth of cancerous tumors and contributes to the pathogenesis of chronic myelogenous leukemia (CML) since it has been found that the BCR-ABL gene that causes CML also increases VEGF [16].…”

“…For its treatment, molecularly directed therapies based on tyrosine kinase inhibitors [14] are used, which block the mechanism of enzymatic action of the BCR-ABL gene fusion protein and are successful in most cases. Those therapies that are based on the use of tyrosine kinase inhibitors such as imatinib mesylate; however, resistance to this drug tends to be developed, both due to intrinsic factors (such as mutations in the same fusion gene or clonal evolution) and extrinsic factors (lower bioavailability of the drug) [13]; therefore, the ATO can also be used for the treatment of CML.…”