Echinomycin protects mice against relapsed acute myeloid leukemia without adverse effect on hematopoietic stem cells.

Abstract

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 hypoxia-inducible factor (HIF)1α inhibitor echinomycin can be used to treat relapsed AML without affecting host HSCs. We show that echinomycin cured 40% to 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 nonleukemic mice in competitive repopulation assays. Importantly, in mice with complete remission, echinomycin appeared to completely eliminate LICs because 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.

• Authors: Yin Wang, Yan Liu, Fei Tang, Kelsie M Bernot, Reuven Schore, Guido Marcucci, Michael A Caligiuri, Pan Zheng, Yang Liu
• Journal: Blood (Blood) Vol. 124 Issue 7 Pg. 1127-35 (Aug 14 2014) ISSN: 1528-0020 [Electronic] United States
• PMID: 24994068 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2014 by The American Society of Hematology.

Chemical References

• Antibiotics, Antineoplastic
• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• Echinomycin

Topics

• Acute Disease
• Animals
• Antibiotics, Antineoplastic (pharmacology)
• Bone Marrow Transplantation
• Echinomycin (pharmacology)
• Flow Cytometry
• Hematopoietic Stem Cells (drug effects, metabolism)
• Hypoxia-Inducible Factor 1, alpha Subunit (antagonists & inhibitors, genetics, metabolism)
• Leukemia, Myeloid (drug therapy, genetics, metabolism)
• Mice, Knockout
• Neoplasm Recurrence, Local
• Neoplastic Stem Cells (drug effects, metabolism)
• RNA Interference
• Remission Induction
• Time Factors
• Treatment Outcome