Sensitizing Dormant Leukemic Cells to Anti-Leukemic Agents By Anne Forde

Ikezoe et al., pp. 2317–2325

Leukemia stem cells are thought to initiate and maintain acute myeloid leukemia (AML). Although remission in AML patients can be as high as 85%, relapses often occur. Eradication of these dormant leukemia stem cells is thought to be critical to avoid clinical relapse.

In this study, Ikezoe et al., investigate whether the prosurvival signal pathways that are found in CD34+/CD38 populations of AML patients are important for dormant leukemia stem cells' resistance to anti-leukemic agents. Leukemia cells isolated from 11 AML patients were sorted into CD34+/CD38 and CD34+/CD38+ populations and the former showed a higher percentage of cells in a dormant state (68 versus 16%). Higher levels of activated signaling molecules JAK2 and STAT5 were also found in CD34+/CD38 than in CD34+/CD38+ populations. CD34+/CD38 cells from 3 different patients proved more resistant to the anti-leukemic agents AraC and the FLT3 kinase inhibitor sunitab relative to their CD34+/CD38+ counterparts. However, this phenomenon could be counteracted when the authors exposed CD34+/CD38 populations to AZ960, a specific inhibitor of JAK2 kinase. When used in combination with either of the two aforementioned anti-leukemic agents, colony formation inhibition went down from 10–15% to 60–70%. The use of AZ960 also stimulated cycling in CD34+/CD38 and the down-regulation of the anti-apoptotic protein Bcl-xL.

“…using a specific inhibitor of this signaling pathway … could sensitize the CD34+/CD38 population to anti-leukemic agents.”

Although the patient sample was small, this study shows that JAK2 and STAT5 signaling may be differentially activated in CD34+/CD38 populations. It appears that using a specific inhibitor of this signaling pathway such as AZ960 could sensitize the CD34+/CD38 population to anti-leukemic agents. Further work is required to confirm these results and elucidate their contribution to the phenomenon of dormant leukemia stem cells.

Hepatocellular Carcinoma: Skipping CirrhosisBy Gina Kirchweger

Ertle et al., pp. 2436–2443

Non-alcoholic fatty liver disease (NAFLD) refers to a spectrum of diseases of the liver ranging from steatosis (fatty infiltration of the liver) to the more serious non-alcoholic steatohepatitis (NASH; inflammation and hepatocyte necrosis). NASH may lead to severe liver scarring and cirrhosis, which comes with its own set of complications, such as hepatocellular carcinoma (HCC). It is the most common cause of elevated liver enzymes in adults in the Western world and its prevalence tracks with increasing body weight. NAFLD is, in fact, regarded as the hepatic manifestation of the metabolic syndrome.

Just as NAFLD, including the more aggressive NASH, has been increasing with the growing epidemic of obesity and diabetes, the incidence of HCC has been steadily rising in the developed word. To pin down any possible connections between the two, Ertle et al. recruited 162 adults with HCC, investigated the underlying etiologies and determined the prevalence of metabolic syndrome and related features within each group.

Illustration 1.

Etiologies of underlying liver diseases for HCC. HCCs were most commonly associated with chronic viral hepatitis. The second leading cause for HCC was non-alcoholic steatohepatitis (NASH), while only 13% had alcoholic steatohepatitis.

As expected, patients with NAFLD/NASH-associated HCC exhibited a higher prevalence of metabolic features (type 2 diabetes mellitus, hypertension, dyslipidemia, and coronary artery disease) when compared to non-NAFLD/NASH-HCC. Surprisingly, however, almost half of all individuals with NAFLD/NASH-associated HCC lacked any sign of cirrhosis, leading the authors to conclude that NAFLD itself may pose a risk factor for HCC, even in the absence of cirrhosis. The complications of NASH, including HCC, are likely to increase as the current obesity epidemic continues to spread unimpeded.

Fighting Cancer with Aspirin By Gina Kirchweger

Dhillon et al., pp. 2444–2452

A recent study, which tracked a group of 25,570 patients, some of whom were randomly assigned to take a daily aspirin to prevent heart attacks or vascular disease, found that those taking aspirin regularly had a 21% lower risk of dying from cancer than those not taking the drug. Benefits were seen after taking aspirin for 5 years for esophageal, pancreatic, brain and lung cancer. In this issue, a prospective cohort study following twice as many patients over 18 years adds prostate cancer to the growing list of cancers positively affected by regular doses of aspirin.

When Dhillon et al. evaluated long-term aspirin use and the incidence of total, high-grade and lethal prostate cancer in 51,520 patients, they observed a 10% reduced risk of prostate cancer associated with the consumption of at least two adult-strength aspirin tablets per week that was further reduced in men over the age of 65 years (15%). The authors also found significant decreases in high-grade (28%) and lethal (29%) prostate cancer risk with dose-response associations for number of tablets per week.

Although a recent international consensus statement stated that aspirin has the potential for chemoprevention, the decision to take aspirin solely to reduce the risk of cancer needs to weigh the risks against the benefits since the regular use of aspirin can have serious side effects, including stomach bleeding and irritation.