Preclinical evaluation of Echinomycin: therapeutic efficacy in relapsed acute myeloid leukemia without adverse effects on host hematopoietic stem cells
Menée à l'aide d'un modèle murin de leucémie myéloïde aiguë récidivante, cette étude suggère l'intérêt de l'echinomycine, un inhibiteur de HIF1 alpha, pour éradiquer les cellules souches leucémiques
Acute myeloid leukemia (AML) often relapses following chemotherapy-induced remission and is generally chemo-resistant. Given the potential role for cancer stem cells in relapse, targeting of the leukemia initiating cell (LIC) in AML may provide improved outcome following remission induction. However, due to overlap in their self-renewal program with normal hematopoietic stem cells (HSCs), therapeutic targeting of the LIC may have an adverse effect on long-term hematopoietic recovery. Here we used a mouse model of relapsed AML to explore whether the HIF1α inhibitor Echinomycin can be used to treat relapsed AML without affecting host HSCs. We show that Echinomycin cured 40-60% of mice transplanted with relapsed AML. Bone marrow cells from the cured mice displayed normal composition of HSCs and their progenitors and were as competent as those isolated from non-leukemic mice in competitive repopulation assays. Importantly, in mice with complete remission, Echinomycin appeared to completely eliminate LICs as no leukemia could be propagated in vivo following serial transplantation. Taken together, our data demonstrate that in a mouse model of relapsed AML, low dose Echinomycin selectively targets LICs and spares normal hematopoiesis.
Blood 2014