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Decoupling of Tumor-Initiating Activity from Stable Immunophenotype In HoxA9-Meis1 Driven AML

Gibbs, K.D., Jager, A., Crespo, O. et al.

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 (TIC) 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.

Citation

Gibbs, K.D., Jager, A., Crespo, O. et al. "Decoupling of Tumor-Initiating Activity from Stable Immunophenotype In HoxA9-Meis1 Driven AML" Cell Stem Cell (2013): 210–7