Arsenic-based therapy shown to help eradicate leukemia-initiating cells

The investigators set out to analyze expression of PML, a tumor suppressor protein that controls fundamental processes such as apoptosis, cellular proliferation and senescence. PML is commonly associated with acute promyelocytic leukemia (APL), in which it leads to the formation of a fusion protein that blocks cell differentiation.

After ascertaining that PML was highly expressed in the LICs of a CML mouse model, Pandolfi’s team also determined that PML is highly expressed in blasts from CML patients and that low PML levels corresponded with patients’ increased response to therapy and overall survival rates.

“We then analyzed LIC function in the absence of PML and revealed that PML has an indispensable role in maintaining LIC quiescence,” he adds. “As a result, PML-deficient LICs grow exhausted over time, becoming incapable of generating CML in the transplanted animals.”

Lastly, the investigators examined the impact of As2O3, an arsenic-based therapy that targets PML for degradation and is currently used for the treatment of acute promyelocytic leukemia. As predicted, inhibition of PML by As2O3 successfully disrupted LICs, increasing the efficacy of the anti-cancer therapy by sensitizing the LICs to pro-apoptopic stimuli.

“It’s actually a very simple concept,” says Pandolfi. “Ninety percent of existing cancer treatments are antiproliferative agents – they target the pool of proliferative cells, leaving behind the dormant LICs.

“But in determining that PML serves to guard the LICs that have been left behind, we also discovered that if we knock out PML [through pharmacologic means], the LICs will lose their braking abilities and run out of gas, thereby commiting the fatal error of proliferation -- and exposing themselves to the deadly effects of cancer therapies.”

Pandolfi’s laboratory is now trying to determine whether PML exerts a similar role in the stem cells of other tissues, as well as in the cancer initiating cells of solid tumors.

“If this turn out to be the case,” he adds, “the transient use of As2O3 may represent a more global strategy to target CICs in other forms of cancer.”

This study was supported by grants from the National Institutes of Health.

Study coauthors include BIDMC Cancer Genetics investigators Keisuke Ito (first author), Rosa Bernardi, and Alessandro Morotti; Sahoko Matsuoka and Yasuo Ikeda of Keio University School of Medicine, Tokyo, Japan; Giuseppe Saglio of the University of Turin, Turin, Italy; Julie Teruya-Feldstein of Memorial Sloan-Kettering Cancer Center, New York, NY; and Jacalyn Rosenblatt and David Avigan of BIDMC’s Division of Hematology and Oncology.

Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School, and consistently ranks among the top four in National Institutes of Health funding among independent hospitals nationwide. BIDMC is clinically affiliated with the Joslin Diabetes Center and is a research partner of the Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. For more information, visit www.bidmc.harvard.edu.