RESUMEN
Epigenetically regulated transcriptional plasticity has been proposed as a mechanism of differentiation arrest and resistance to therapy. BCR-ABL leukemias result from leukemic stem cell/progenitor transformation and represent an opportunity to identify epigenetic progress contributing to lineage leukemogenesis. Primary human and murine BCR-ABL+ leukemic progenitors have increased activation of Cdc42 and the downstream atypical protein kinase C (aPKC). While the isoform aPKCζ behaves as a leukemic suppressor, aPKCλ/ι is critically required for oncogenic progenitor proliferation, survival, and B-cell differentiation arrest, but not for normal B-cell lineage differentiation. In vitro and in vivo B-cell transformation by BCR-ABL requires the downregulation of key genes in the B-cell differentiation program through an aPKC λ/ι-Erk dependent Etv5/Satb2 chromatin repressive signaling complex. Genetic or pharmacological targeting of aPKC impairs human oncogenic addicted leukemias. Therefore, the aPKCλ/ι-SATB2 signaling cascade is required for leukemic BCR-ABL+ B-cell progenitor transformation and is amenable to non-tyrosine kinase inhibition.
Asunto(s)
Leucemia/patología , Proteína Quinasa C/metabolismo , Animales , Linfocitos B/metabolismo , Linfocitos B/patología , Transformación Celular Neoplásica/metabolismo , Cromatina/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/fisiología , Epigénesis Genética , Proteínas de Fusión bcr-abl/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Leucemia/metabolismo , Proteínas de Unión a la Región de Fijación a la Matriz/genética , Proteínas de Unión a la Región de Fijación a la Matriz/metabolismo , Proteínas de Unión a la Región de Fijación a la Matriz/fisiología , Ratones , Células Precursoras de Linfocitos B/metabolismo , Proteína Quinasa C/fisiología , Transducción de Señal , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/fisiología , Proteína de Unión al GTP cdc42/genética , Proteína de Unión al GTP cdc42/metabolismoRESUMEN
This article tends to illustrate the coordination mechanisms used through an example centred on a case study of a 65 year-old patient who presents obesity, hypertension, high cardiovascular risk, alcoholism, smoking and silent ischaemic strokes; divorced twice and with five children. After his last separation 8 years ago he moved to his father's house. While his father was still alive his health situation was stable and monitored by professionals of the primary care team. He was recently referred to the Social Worker at the Health Centre due to his lack of personal hygiene and housing. The interdisciplinary work of the Social Worker and Community Nurse Case Manager resulted in a shared action plan. His father died a year ago and since then there was no news of the patient in the health centre and also he did not collect his medication from the pharmacy. The house was owned by inheritance by the smallest of the four brothers, who had threatened to expel him. In the interview, the brother claimed that he didn't want to be helped and only received visits from one of his sons occasionally to receive money. Primary care professionals visited him several times at home. The patient was cooperative and engaged when preparing a joint plan with the professionals involved. This joint plan allowed to activate the care coordination for a successful management of his chronic conditions.
