Targeting leukemic stem cells by breaking their dormancy

Abstract

Transient or long-term quiescence, the latter referred to as dormancy are fundamental features of at least some adult stem cells. The status of dormancy is likely a critical mechanism for the observed resistance of normal HSCs and leukemic stem cells (LSCs) to anti-proliferative chemotherapy. Recent studies have revealed cytokines such as Interferon-alpha (IFNα) and G-CSF as well as arsenic trioxide (As(2)O(3)) to be efficient agents for promoting cycling of dormant HSCs and LSCs. Most interestingly, such cell cycle activated stem cells become exquisitely sensitive to killing by different chemotherapeutic agents, suggesting that dormant LSCs in patients may be targeted by a sequential two-step protocol involving an initial activation by IFNα, G-CSF or As(2)O(3), followed by targeted chemotherapy.

Figure 1

A positive feedback loop leads to the activation of dormant and homeostatic HSCs in response to hematopoietic cell loss. Dormant and homeostatic HSCs reside in distinct bone marrow niches. During homeostasis, dormant HSCs (dHSCs) remain inactive, whereas homeostatic HSCs (hHSCs) divide and self‐renew if the number of progenitors and differentiated cells drop below a homeostatic threshold level. The self‐renewal activity of hHSCs results in the constant generation of rapidly dividing progenitors, which eventually differentiate into mature blood cells. Injury to the hematopoietic system (i.e. irradiation, chemotherapy or bleeding) results in severe loss of hematopoietic cells, inducing strong positive feedback loops (red arrow). As a consequence, dHSCs and hHSCs exit their niches and undergo major self‐renewing divisions, thus replenishing first the progenitor compartment, followed by the recovery of all hematopoietic cell populations and return to homeostasis.

Figure 2

IFNα induces activation of HSCs in vivo. In vivo treatment of mice with the cytokine IFNα induces cell cycle entry of dormant and homeostatic HSCs as well as multipotent progenitors (MPPs). IFNα signaling leads to rapid phosphorylation of STAT1 and PKB, as well as activation of a set of IFNα target genes. The IFNα response is also associated with a robust up‐regulation of the stem cell marker Sca‐1 (red) on the cell surface of stimulated cells. This up‐regulation of Sca‐1 is required for the IFNα‐mediated activation and proliferation of stem/progenitors, since dHSCs lacking Sca‐1 no longer divide in response to IFNα.

Figure 3

A two‐step therapy strategy to target leukemic stem cells: three examples. a. Even though leukemic stem cells (LSCs) might only be a minority within the malignant leukemic clone, they show significant resistance to anti‐proliferative chemotherapy. Their resistance is considered to be the cause of frequently observed tumor relapse. Several reasons for this resistance have been suggested amongst which is the quiescent or dormant state of LSCs. Thus, if dormancy is a main reason for LSC resistance to chemotherapy one could postulate a two‐step therapy model by which the dormant LSCs can be targeted; activators of quiescence first induce activation of dormant LSCs, followed by targeted therapy. This therapy model would not only eliminate the bulk of the leukemia, but likely also activated LSCs, thus reducing the probability of relapse of the leukemia. Three possible combinations have recently been suggested: b. IFNα efficiently activates dormant mouse HSCs in vivo via the up‐regulation of Sca‐1, thus making them susceptible to elimination by 5‐FU. c. Inhibition of PML by treatment with arsenic trioxide (As2O3) induces activation of LSCs facilitating their efficient elimination by the chemotherapeutic agent Ara‐C. d. G‐CSF induces activation and mobilization of dormant HSCs and LSCs. Combined treatment of G‐CSF and Imatinib in vitro efficiently kills dormant CML LSCs, whereas G‐CSF treatment in vivo, followed by cytarabine, leads to the elimination of AML LSCs in a xenograft model for AML.