Charles Parker, MD

2010-01-01

Dr. Parker indicated no relevant conflicts of interest.

Essers MAG, Offner S, Blanco-Bose, WE, et al. IFNα activates dormant haematopoietic stem cells in vivo. Nature. 2009;458:904-08.

Taku S, Onai N, Yoshihara H, et al. Interferon regulatory factor-2 protects quiescent hematopoietic stem cells from type I interferon–dependent exhaustion. Nat Med. 2009;15:696-700.

Although type I interferons (INFα and INFβ) have been used therapeutically for three decades and have been tested against a variety of solid tumors and hematologic malignancies, overall, their clinical value has been modest. The most notable success for INF has been realized in the treatment of myeloproliferative disorders. Until the development of imatinib, INFα, in combination with cytosine arabinoside, was the standard of care for CML. And recent studies demonstrate efficacy in the treatment of polycythemia vera (PV) and essential thrombocytosis (ET), including induction of molecular remissions in PV patients with mutant JAK2 (JAK2V617F).¹ Considerable debate surrounds the basis of INF’s anti-neoplastic activity, as the protein has both antiproliferative and immunomodulatory properties. The marrow toxic effects are well known to clinicians, as patients treated with INFα often develop dose-limiting cytopenias. The myelosuppressive effect has been attributed to the antiproliferative properties of the protein, but two recent studies identified a novel, unanticipated mechanism that likely contributes to the apparent marrow toxicity of INFα and suggested that the process can be exploited to enhance the efficacy of cytotoxic chemotherapy.

A central tenant of hematopoietic homeostasis is that a pool of hematopoietic stem cells (HSCs) with selfrenewal capacity (~10% of the total population of HSCs) exists in a relatively quiescent state within the marrow (Figure). In the setting of marrow stress, signals are delivered to the HSC pool that cause cells to exit the quiescent state and begin dividing to yield progeny committed to differentiation, thereby augmenting the hematopoietic response to injury or infection. Despite the obvious biologic and pathobiologic importance, the process that mediates the exit of HSCs out of the dormant state has remained largely enigmatic. Now, working independently and using different murine model systems, a group of German/Swiss investigators and scientists from Japan have shown that acute treatment with INFα induces HSCs to exit the quiescent state and enter a proliferative state characterized by active cell cycling and differentiation, with chronic stimulation with INFα resulting in HSC exhaustion (Figure). The factors involved in INFα-mediated activation of the dormant HSC pool (Figure legend) were identified through a series of insightful, rigorous studies that relied primarily on transplantation experiments in knockout mice.

A potentially exciting clinical application of these observations is suggested by the results of longitudinal followup of patients with CML initially treated with INFα and treated subsequently with imatinib.² A handful of those patients have had a sustained molecular remission despite discontinuation of imatinib,^3,4 while patients treated with imatinib only invariably relapse if the drug is discontinued. One interpretation of those observations is that treatment with INFα caused the CML stem cells to exit their dormant state, during which they were resistant to imatinib, and enter into a proliferative and differentiating state in which they became susceptible to the toxic effects of the drug. Conceivably, the strategy of using INFα to stimulate proliferation and differentiation of quiescent neoplastic HSCs could be applied to other hematologic malignancies and thereby enhance the effects of available cytotoxic chemotherapeutic agents. Studying the effects of INFα on human hematopoietic stems cells may soon be feasible, as plans are currently underway to initiate a multinational phase III clinical trial comparing pegylated INFα with hydroxyurea for treatment of patients with high-risk JAK2V617F+ PV and ET. The elegant studies of Essers et al. and Taku and colleagues have illuminated another milestone on the shadowy road to discovery of the beguiling properties of interferon.

1. Kiladjian JJ, Cassinat B, Chevret S, et al. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood. 2008;112:3065-72.
2. Passegué E, Ernst P. IFN-α wakes up sleeping hematopoietic stem cells. Nat Med. 2009;15:612-13.
3. Alimena G, Breccia M, Luciano L, et al. Imatinib mesylate therapy in chronic myeloid leukemia patients in stable complete cytogenic response after interferon-alpha results in a very high complete molecular response rate. Leuk Res. 2008;32:255-61.
4. Rousselot P, Huguet F, Rea D, et al. Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood. 2007;109:58-60.

Under homeostatic conditions, a balance is maintained between two pools of HSCs. The quiescent pool is characterized by high self-renewal, low cell cycling activity (top panel). To maintain steady state, some HSCs exit the quiescent pool and begin to actively cycle and differentiate (top panel). Treatment with INFα changes the dynamics by stimulating quiescent cells to enter the cycling/differentiating pool (bottom panel). The response of quiescent HSCs to INFα involves both positive and negative regulatory elements. Binding of INFα to its receptor (IFNAR) stimulates a signaling cascade that results in phosphorylation of STAT-1 and -2 which then participate in HSC activation in two ways: 1) they phosphorylate other factors involved in proliferation, and 2) they form a complex with interferon regulator factor 9 (the trimolecular complex is called interferon-stimulated gene factor-3, ISGF3) that binds to the interferon-stimulated responsive element (ISRE) in genes whose transcription is regulated by INF. A negative regulator, interferon regulatory factor 2 (IRF2), also effects INFα homeostasis by competing with IRF9 for binding to the ISRE. Because IRF2 lacks binding sites for STATs, it cannot form an ISGF3 and therefore does not support transcription. Inactivation of IRF2 results in depletion of the dormant HSC pool because constitutively generated INFα activity proceeds unopposed. Chronic treatment with INFα leads to exhaustion of the quiescent HSC pool (bottom panel).

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