Acute myeloid leukemia: therapeutic targeting of stem cells

ABSTRACT

Introduction

Despite advances in the treatment of acute myeloid leukemia (AML), long-term survival remains low. In 1994, it was proposed that leukemic stem cells (LSCs) played a key role in relapsed and refractory disease. LSCs are capable of self-renewal, proliferation, differentiation, immune evasion, and drug resistance through several unique mechanisms. More recent leukemia drug development initiatives have included efforts to target LSCs. With LSCs, the challenge with such drug design is finding a way to selectively target LSCs while sparing normal hematopoietic stem cells (HSCs).

Areas covered

In this review, we explore the evolving knowledge of the unique LSC biology and physiology in the scientific literature, while noting the several agents that have been designed throughout the years to target this subgroup of leukemic cells. Our review includes discussion on chimeric antigen receptor T cells, monoclonal antibodies, antibody-drug conjugates against cell surface markers, signaling pathway targets, pro-apoptotic agents, epigenetic regulators, and more.

Expert opinion

As our understanding of the intricate pathophysiology of LSCs continues to grow, it is clear that targeting such heterogenous cells successfully will require a thoughtful and multi-modal approach.

KEYWORDS:

• Leukemic stem cell
• acute myeloid leukemia
• targeted therapy
• hematopoiesis

Declaration of interest

M Konopleva has Consultancy roles with (includes expert testimony): AbbVie, Genentech, F.

Hoffman La-Roche, Stemline Therapeutics, Amgen, Forty-Seven, Kisoji; Janssen.

Equity ownership Stocks in Reata Pharmaceuticals.

Funding research from AbbVie, Genentech, F. Hoffman La-Roche, Eli Lilly, Cellectis, Calithera, Ablynx, Stemline Therapeutics, Agios, Ascentage, Astra Zeneca; Rafael Pharmaceutical; Sanofi, Forty-Seven.

Honoraria from Forty-Seven; F. Hoffman LaRoche.

Patents and royalties with Reata Pharmaceuticals, Novartis and Eli Lilly.

Membership on Board of Directors or advisory committee: Stemline Therapeutics, F.

Hoffman La-Roche; Janssen.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Article highlights

• Effective treatment of acute myeloid leukemia (AML) requires successful targeting of leukemic stem cells (LSCs).

• From the emerging therapies, Chimeric antigen receptor (CAR) T cells and bispecific T-cell engager molecules (BiTEs), targeting LSC antigens such as Tim3, CLL-1, CD123 and CD70, seem the most promising.

• Additional agents exploit the relationship between LSCs and the bone marrow niche to prevent adhesion.

• Intracellular pathways vital for LSC survival serve as areas for further drug development, including JAK-STAT, NF-kB, PI3K/Akt/Nrf2, Notch, Hedgehog, and Wnt-β-catenin signaling.

• LSC dependence on oxidative phosphorylation functions as an additional target with specific attention to mitochondrial enzymes.

Additional information

Funding

Dr. Konopleva has grant funding from (1) IRG CD200 Stem Cell Spec Mech - Overexpression of CD200 is a Stem Cell- Specific Mechanism of Immune Evasion in AML and (2) CCSG - P30 CA016672.