Decoupling of Tumor-Initiating Activity from Stable Immunophenotype in HoxA9-Meis1-Driven AML
Menée sur un modèle murin de leucémie myéloïde aiguë, cette étude montre qu'une activité initiatrice de tumeurs est présente dans trois compartiments cellulaires correspondant à des lignées hématopoïétiques distinctes et met en évidence les réseaux de signalisation communs à ces cellules initiatrices de tumeurs
Increasing evidence suggests tumors are maintained by cancer stem cells; however, their nature remains controversial. In a HoxA9-Meis1 (H9M) model of acute myeloid leukemia (AML), we found that tumor-initiating activity existed in three, immunophenotypically distinct compartments, corresponding to disparate lineages on the normal hematopoietic hierarchy stem/progenitor cells (Lin kit+) and committed progenitors of the myeloid (Gr1+kit+) and lymphoid lineages (Lym+kit+). These distinct tumor-initiating cells (TICs) clonally recapitulated the immunophenotypic spectrum of the original tumor in vivo (including cells with a less-differentiated immunophenotype) and shared signaling networks, such that in vivo pharmacologic targeting of conserved TIC survival pathways (DNA methyltransferase and MEK phosphorylation) significantly increased survival. Collectively, H9M AML is organized as an atypical hierarchy that defies the strict lineage marker boundaries and unidirectional differentiation of normal hematopoiesis. Moreover, this suggests that in certain malignancies tumor-initiation activity (or cancer stemness ) can represent a cellular state that exists independently of distinct immunophenotypic definition. º In H9M AML, tumor-initiating activity (TIA) and lineage differentiation are separate º TIA exists in three compartments, corresponding to distinct hematopoietic lineages º Such tumor-initiating cells (TIC) share signaling networks and survival pathways º Targeting pathways conserved between TIC in vivo significantly increases survival
Cell stem cell , article en libre accès, 2011