Tesis doctoral de Paula Aranaz Oroz
Genetic mechanisms of activation of cell signaling pathways in bcr-abl1 negative chronic myeloproliferative neoplasms chronic myeloproliferative neoplasms (cmpns) are clonal disorders of the hematopoietic stem cells, characterized by abnormal proliferation and survival of one or more cells of the myeloid lineage. Bcr-abl1 negative cmpns are a heterogeneous group of diseases for which the molecular pathogenesis is not well understood. Some genetic alterations have been described, most of them activating some tyrosine kinase genes playing a role similar to abl1 in cml. In this study, we have analyzed all genes from tks families fgfr (fgfr1, fgfr2, fgfr3 and fgfr4), abl (abl1 and abl2), syk (syk and zap70) and egfr by fish (to detect cryptic rearrangements), dhplc (to detect sequence mutations) and in some of them by rq-pcr (to analyze changes in gene expression) on samples from 44 bcr-abl1 negative and v617fjak2 negative cmpns. No changes have been identified in these genes, so lesions in other genes must be involved in the pathogenesis of these diseases. In addition we also analysed by dhplc c-cbl, cbl-b and cbl-c, genes that belong to a family of e3-ubiquitin ligases mutated in these neoplasms, in samples from 377 patients of bcr-abl1 negative cmpns (145 v617fjak2 negatives and 232 v617fjak2 positives). We have found five missense mutations in c-cbl and one in cbl-b. Three of the c-cbl mutations and the cbl-b mutation were identified in v617fjak2 positive patients. The functional analysis of these mutations showed that all c-cbl mutations (but not cbl-b and other cbl-c changes) promoted a significant increase in the rate of proliferation induced by il3.
Datos académicos de la tesis doctoral «Mecanismos genéticos de activación de vías de señalización celular en neoplasias mieloproliferativas crónicas bcr-abl1 negativas«
- Título de la tesis: Mecanismos genéticos de activación de vías de señalización celular en neoplasias mieloproliferativas crónicas bcr-abl1 negativas
- Autor: Paula Aranaz Oroz
- Universidad: Navarra
- Fecha de lectura de la tesis: 04/05/2011
Dirección y tribunal
- Director de la tesis
- José Luis Vizmanos Pérez
- Tribunal
- Presidente del tribunal: Francisco javier Novo villaverde
- Ana Rouzaut subira (vocal)
- Elena Fernández ruiz (vocal)
- José Luis Fernández luna (vocal)