Treatment for chronic myeloid leukemia (CML) has evolved from chemotherapy (busulfan, hydroxyurea) to interferon-α (IFNα), and finally to tyrosine kinase inhibitors such as imatinib. Although imatinib has profoundly improved outcomes for patients with CML, it has limitations. Most significantly, imatinib cannot eradicate CML primitive progenitors, which likely accounts for the high relapse rate when imatinib is discontinued. IFNα, unlike imatinib, preferentially targets CML stem cells. Early studies with IFNα in CML demonstrated its ability to induce cytogenetic remission. Moreover, a small percentage of patients treated with IFNα were able to sustain durable remissions after discontinuing therapy and were probably cured. The mechanisms by which IFNα exerts its antitumor activity in CML are not well understood; however, activation of leukemia-specific immunity may have a role. Some clinical studies have demonstrated that the combination of imatinib and IFNα is superior to either therapy alone, perhaps because of their different mechanisms of action. Nonetheless, the side effects of IFNα often impede its administration, especially in combination therapy. Here, we review the role of IFNα in CML treatment and the recent developments that have renewed interest in this once standard therapy for patients with CML.

Interferon-alpha (IFNα) was once the standard of frontline treatment for chronic myeloid leukemia (CML). Its pleiotropic mechanism of action in CML includes immune activation and specific targeting of CML stem cells. Early studies of IFNα in CML demonstrated that patients in chronic phase could attain extremely stable remissions, which correlated with long-term survival. Some patients even sustained their remission after discontinuing therapy, but the mechanism underlying this phenomenon is not well understood. Today, BCR-ABL tyrosine kinase inhibitors (TKIs), such as imatinib, induce remarkable responses in CML patients and have become the mainstay of CML therapy. Although TKIs target the pathogenic BCR-ABL protein in CML, they cannot fully eradicate CML stem cells. Some of the clinical trials testing IFNα plus imatinib combination therapy suggest that addition of IFNα increases the speed and rate of responses with imatinib therapy. However, the undesirable side effects of IFNα can make this therapy difficult to deliver, and the optimal therapeutic window for using IFNα in combination therapy is unknown. Further studies are needed to clarify the best niche for IFNα use in CML.

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Spatial variations in the salinity of pore waters in sedimentary basins can provide important insight into basinscale hydrogeologic processes. Although there have been numerous studies of brine seeps in the deep water Gulf of Mexico, much less is known about porewater salinities in the vast areas between seeps. A study has been made of spatial variation in pore water salinities in sediments in an approximately 500 km by 200 km area of the northern deep water (water depth >500 m) Gulf of Mexico sedimentary basin (GOM) to provide insight into pathways and mechanisms of solute transport in this portion of the basin. A second objective was to document salinities in the upper 500 m of the sedimentary section, the approximate depth to which methane hydrates, a potential future energy resource, may be stable. Elevated salinities would reduce the P-T stability range of hydrates. Salinities were calculated from borehole logs using a dual electrical conductivity model. Even though much of the northern GOM is underlain by allochthonous salt most of the undisturbed shallow sedimentary section has not been permeated by hypersaline waters. These waters are limited to areas near brine seeps. Hypersaline waters having salinities in excess of 100 g l )1 become more common at subseafloor depths of 2 km and greater. A field study at Green Canyon 65 and published numerical simulations of fluid flow above tabular salt bodies suggest that brines produced by salt dissolution migrate laterally and pond above salt and ⁄ or within minibasins and that the dominant mechanism of vertical solute transport is a combination of compaction-driven advection and diffusion, not large-scale thermohaline overturn. Superimposed on this diffuse upward flux of dissolved salt is the more focused and localized expulsion of saline fluids up faults.

Chronic myeloid leukemia (CML) is characterized by the chromosomal translocation 9;22, known as the Philadelphia chromosome (Ph), which produces the BCR-ABL fusion tyrosine kinase. Although well-managed by BCR-ABL tyrosine kinase inhibitors (TKIs), treatment fails to eliminate Ph + primitive progenitors, and cessation of therapy frequently results in relapse. The p53 protein is an important regulator of cell cycle and apoptosis. The small molecules MI-219 target the interaction between p53 and its negative regulator HDM2, leading to its stabilization and activation. We show that treatment with MI-219 reduced the number of CML cells in both in vitro and in vivo settings but not that of normal primitive progenitors, and activated different gene signatures in CML potentially explaining the differential impact of this agent on each population. Our data suggest that a p53-activating agent may be an effective approach in the management and potential operational cure of CML.