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Arsenic-based therapy shown to help eradicate leukemia-initiating cells
Date:5/12/2008

ICs, with their unique quiescent properties, resemble an automobile with an endless supply of fuel and a sturdy set of brakes: They sit quietly idling in place, waiting to reinitiate malignancy after a period of remission.

Pandolfis laboratory has been working to develop new therapeutic approaches to target LICs and thereby treat chronic myeloid leukemia (CML), one of the most extensively investigated of stem cell disorders. CML is typically treated with the targeted therapy imatinib (Gleevec), a tyrosine kinase inhibitor.

Gleevec does dramatically improve prognosis of CML patients, notes Pandolfi. But, unfortunately, Gleevec is not curative in most cases. Because it targets only dividing cells, the pool of quiescent LICs are able to remain intact. As a result, when Gleevec therapy is discontinued, the cancer almost inevitably relapses.

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, Pandolfis 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 P
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Contact: Bonnie Prescott
bprescot@bidmc.harvard.edu
617-667-7306
Beth Israel Deaconess Medical Center
Source:Eurekalert

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