Les syndromes myélodysplasiques (SMD) sont des maladies hétérogènes de la cellule souche hématopoïétique caractérisées par une dysplasie myéloïde et un excès d’apoptose des précurseurs ...hématopoïétiques. Les voies de signalisation de l’apoptose ciblent le réticulum endoplasmique et la mitochondrie et sont activées en aval du récepteur à domaine de mort Fas. Il existe une grande instabilité génomique et certains événements moléculaires observés au cours de ces maladies plus fréquemment au stade de la transformation en leucémie aiguë myéloïde (LAM), tels que la surexpression d’oncogènes
(EVI-1), l’expression ectopique de gènes non hématopoïétique
(HOXD13), l’expression de gènes en conditions d’haplo-insuffisance
(NPM1, RPS14) ont été utilisés pour générer des modèles murins de SMD ou SMD/LAM. Ces anomalies moléculaires peuvent altérer le transport des protéines et des ARN, la biogenèse des ribosomes, la transcription, la signalisation induisant la prolifération de cellules mal différenciées, un stress cellulaire et une apoptose et contribuant au phénotype. La sélection clonale d’une cellule souche hématopoïétique nécessiterait un événement primaire encore non identifié
Myelodysplastic syndromes are heterogeneous hematopoietic stem cell diseases characterized by myeloid dysplasia and increased apoptosis. Pathways to death targeting mitochondria are activated downstream the death receptor, Fas and the endoplasmic reticulum. Rare molecular events like overexpression of oncogenes, ectopic expression of non hematopoietic genes, gene expression in conditions of haploinsufficiency, identified in these diseases have been used to generate mouse models, which recapitulate the features of MDS or MDS/AML. These molecular defects may alter protein-RNA transport, ribosome biogenesis, transcription and signalling, leading to block of maturation, cellular stress and apoptosis. Clonal selection of hematopoietic stem cell requests a still unknown initiating event.
AMP activated protein kinase (AMPK) is a critical energy sensor, regulating signaling networks involved in pathology including metabolic diseases and cancer. This increasingly recognized role of AMPK ...has prompted tremendous research efforts to develop new pharmacological AMPK activators. To precisely study the role of AMPK, and the specificity and activity of AMPK activators in cellular models, genetic AMPK inactivating tools are required. We report here methods for genetic inactivation of AMPK \(\alpha1/ \alpha2\) catalytic subunits in human cell lines by the CRISPR/Cas9 technology, a recent breakthrough technique for genome editing.
Recent clinical trials using immunotherapy have demonstrated its potential to control cancer by disinhibiting the immune system. Immune checkpoint blocking (ICB) antibodies against ...cytotoxic-T-lymphocyte-associated protein 4 or programmed cell death protein 1/programmed death-ligand 1 have displayed durable clinical responses in various cancers. Although these new immunotherapies have had a notable effect on cancer treatment, multiple mechanisms of immune resistance exist in tumours. Among the key mechanisms, myeloid cells have a major role in limiting effective tumour immunity. Growing evidence suggests that high infiltration of immune-suppressive myeloid cells correlates with poor prognosis and ICB resistance. These observations suggest a need for a precision medicine approach in which the design of the immunotherapeutic combination is modified on the basis of the tumour immune landscape to overcome such resistance mechanisms. Here we employ a pre-clinical mouse model system and show that resistance to ICB is directly mediated by the suppressive activity of infiltrating myeloid cells in various tumours. Furthermore, selective pharmacologic targeting of the gamma isoform of phosphoinositide 3-kinase (PI3Kγ), highly expressed in myeloid cells, restores sensitivity to ICB. We demonstrate that targeting PI3Kγ with a selective inhibitor, currently being evaluated in a phase 1 clinical trial (NCT02637531), can reshape the tumour immune microenvironment and promote cytotoxic-T-cell-mediated tumour regression without targeting cancer cells directly. Our results introduce opportunities for new combination strategies using a selective small molecule PI3Kγ inhibitor, such as IPI-549, to overcome resistance to ICB in patients with high levels of suppressive myeloid cell infiltration in tumours.
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