SIGNALING PROPENSITY IN THE MICROENVIRONMENT OF B CELL CHRONIC LYMPHOCYTIC LEUKEMIA

Descripción del proyecto

La función de las interacciones microambientales en la leucemia linfocítica crónica

La leucemia linfocítica crónica (LLC) es la forma de leucemia más común entre los adultos del mundo occidental. Un componente crucial en la patogénesis de la LLC es la activación de la señalización de los receptores presentes en los linfocitos B que tiene lugar en los ganglios linfáticos, y en el contexto de otras interacciones microambientales (como la interacción entre la LLC y los linfocitos T). En el proyecto LeukemiaEnviron, financiado con fondos europeos, se investiga cómo se comportan las células de la LLC en un microambiente formado por nichos inmunitarios. Se incluye el análisis de muestras de LLC en distintos momentos del desarrollo de la enfermedad, durante terapias dirigidas contra el microambiente, y la comparación de las células de la LLC en los ganglios linfáticos y la sangre periférica. Los resultados pueden tener importantes ramificaciones clínicas y los investigadores aspiran a desarrollar también un nuevo modelo murino de la enfermedad.

Objetivo

B cell chronic lymphocytic leukemia (CLL) is the most frequent leukemia in adults. CLL cells are characterized by their universal dependency on pro-survival and pro-proliferative signals from immune niches. To achieve this they constantly re-circulate between blood and lymph nodes, which is inhibited by novel microenvironment-targeting therapies such as “BCR inhibitors”. We aim to reveal how the malignant B cells change the propensity of their signalling pathways in response to the different microenvironments such as peripheral blood vs lymph node to obtain the proliferative signals. This is of major relevance for CLL, but also transferable to the biology of some other B cell malignancies and/or normal B cells. We analyzed the “finger print” of microenvironmental interactions in many CLL samples at various times during the disease course or during therapy. The obtained data led us to hypothesize on the mechanisms of regulation of signalling propensity of two pathways that are responsible for proliferation and survival of CLL cells, namely B Cell Receptor (BCR) signalling and signals from T-cells mediated by CD40/IL4. In aim 1 we hypothesize that CD20 is one of the key proteins involved in CLL cell activation, and influences BCR and interleukin signalling (see figure). This has important therapeutic implication since CD20 is used as a therapeutic target for 20 years (rituximab), but its function in CLL/normal B cells is unknown. In aim 2 we hypothesize that miR-29 acts a key regulator of T-cell signalling from CD40 and down-stream NFkB activation (see figure). This represents the first example of miRNAs‘ role in the propensity of T-cell interaction, and could be also utilized therapeutically. In aim 3 we will integrate our data on microenvironmental signaling (aim 1+2) and develop a first mouse model for PDX that would allow stable engraftment of primary CLL cells. Currently, CLL is non-transplantable to any animal model which complicates studies of its biology.