Review
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. Oct 26, 2016; 8(10): 316-331
Published online Oct 26, 2016. doi: 10.4252/wjsc.v8.i10.316
Update on acute myeloid leukemia stem cells: New discoveries and therapeutic opportunities
Maximilian Stahl, Tae Kon Kim, Amer M Zeidan
Maximilian Stahl, Tae Kon Kim, Amer M Zeidan, Section of Hematology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510-3222, United States
Author contributions: Stahl M and Zeidan AM wrote the first draft of the manuscript; Stahl M, Kim TK and Zeidan AM edited the manuscript.
Conflict-of-interest statement: Amer M Zeidan receives Honoraria from Ariad, Pfizer, Incyte and Celgene. Maximilian Stahl and Tae Kon Kim have no conflict of interests to declare for this article.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Amer M Zeidan, MBBS, Assistant Professor, Section of Hematology, Department of Internal Medicine, Yale School of Medicine, 300 George Street, New Haven, CT 06510-3222, United States. amer.zeidan@yale.edu
Telephone: +1-203-2004363 Fax: +1-203-2002360
Received: May 23, 2016
Peer-review started: May 23, 2016
First decision: July 6, 2016
Revised: August 11, 2016
Accepted: August 27, 2016
Article in press: August 29, 2016
Published online: October 26, 2016
Abstract

The existence of cancer stem cells has been well established in acute myeloid leukemia. Initial proof of the existence of leukemia stem cells (LSCs) was accomplished by functional studies in xenograft models making use of the key features shared with normal hematopoietic stem cells (HSCs) such as the capacity of self-renewal and the ability to initiate and sustain growth of progenitors in vivo. Significant progress has also been made in identifying the phenotype and signaling pathways specific for LSCs. Therapeutically, a multitude of drugs targeting LSCs are in different phases of preclinical and clinical development. This review focuses on recent discoveries which have advanced our understanding of LSC biology and provided rational targets for development of novel therapeutic agents. One of the major challenges is how to target the self-renewal pathways of LSCs without affecting normal HSCs significantly therefore providing an acceptable therapeutic window. Important issues pertinent to the successful design and conduct of clinical trials evaluating drugs targeting LSCs will be discussed as well.

Keywords: Leukemia stem cells, Cancer stem cells, Acute myeloid leukemia, Stem cell niche, Xenotransplantation, Plerixafor, NF-κB, C-X-C chemokine receptor type 4

Core tip: Leukemia stem cell (LSC) directed therapy targets: (1) Cell surface markers expressed on LSC: CD33, CD44, CD123, CD47, etc.; (2) Crucial pathways for maintenance of their stemness: NF-κB, PI3K/AKT/mTOR and bcl-2; and (3) Interactions between LSC in the bone marrow niche: LSC mobilization with granulocyte-colony stimulating factor and inhibition of LSC homing to the bone marrow by interrupting the C-X-C chemokine receptor type 4-CXCL12 and VCAM-VLA4 axis.