Targeting the leukemic stem cell: the Holy Grail of leukemia therapy

Abstract

Since the discovery of leukemic stem cells (LSCs) over a decade ago, many of their critical biological properties have been elucidated, including their distinct replicative properties, cell surface phenotypes, their increased resistance to chemotherapeutic drugs and the involvement of growth-promoting chromosomal translocations. Of particular importance is their ability to transfer malignancy to non-obese diabetic-severe combined immunodeficient (NOD-SCID) mice. Furthermore, numerous studies demonstrate that acute myeloid leukemia arises from mutations at the level of stem cell, and chronic myeloid leukemia is also a stem cell disease. In this review, we will evaluate the main characteristics of LSCs elucidated in several well-documented leukemias. In addition, we will discuss points of therapeutic intervention. Promising therapeutic approaches include the targeting of key signal transduction pathways (for example, PI3K, Rac and Wnt) with small-molecule inhibitors and specific cell surface molecules (for example, CD33, CD44 and CD123), with effective cytotoxic antibodies. Also, statins, which are already widely therapeutically used for a variety of diseases, show potential in targeting LSCs. In addition, drugs that inhibit ATP-binding cassette transporter proteins are being extensively studied, as they are important in drug resistanceFa frequent characteristic of LSCs. Although the specific targeting of LSCs is a relatively new field, it is a highly promising battleground that may reveal the Holy Grail of cancer therapy.

AMP-dependent kinase/mammalian target of rapamycin complex 1 signaling in T-cell acute lymphoblastic leukemia: therapeutic implications

“…48 Therefore, strategies that eliminate these cells could have significant clinical implications. On one side we were able to demonstrate that metformin targeted the SP of T-ALL cells, which could be enriched in CSCs.…”

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

“…The PI3K/PTEN/Akt/mTOR pathway, and specifically PTEN levels, may be critical for the development of CICs. 175,176 The concept that the PI3K/PTEN/Akt/mTOR pathway serves as a therapeutic target in CICs is beginning to emerge. CICs have unique properties as they can be both quiescent and also resistant to chemotherapeutic-and hormonal-based drugs.…”

Targeted inhibition of mTORC1 and mTORC2 by active-site mTOR inhibitors has cytotoxic effects in T-cell acute lymphoblastic leukemia

“…45 The difficulty in eradicating tumors might result from the conventional treatments targeting the bulk of the tumor cells, but not the LIC. 46 Therefore, strategies that eliminate these cells could have significant clinical implications. All of the active site mTOR inhibitors we tested, induced apoptosis in a T-ALL lymphoblast sub-population (CD34 þ /CD7 À /CD4 À ), which has been reported to be enriched in LIC in pediatric patients.…”