Unexpected discovery demonstrates key role for Promyelocytic Leukemia (PML) tumour suppressor gene
In both leukaemia and solid tumours, there exists a small subgroup of cancer stem cells, known as either cancer initiating cells (CICs) or leukaemia initiating cells (LICs), which are impervious to conventional chemotherapy and undaunted by targeted cancer therapies. When a leukaemia patient relapses following a period of remission, it is the LICs that cause the disease’s re-emergence.
The secret to the survival abilities of these cells has been unclear. But in a paradoxical discovery, a research team led by investigators at Beth Israel Deaconess Medical Center (BIDMC) has found that a tumour suppressor protein known as PML appears to be the factor that enables LICs to maintain their quiescence – the inert state that protects them from being destroyed by cancer therapies – and suggests that inhibition of PML is a promising target for new therapeutics.
Their findings, which appear in today’s advance on-line issue of the journal Nature, additionally demonstrate that PML can be degraded with an arsenic-based agent used in traditional Chinese medicine. Importantly, when combined with chemotherapy, the arsenic-based therapy -- already proven safe and non-toxic in clinical trials -- can successfully treat chronic myeloid leukaemia.
“Leukaemia initiating cells share many properties of normal haematopoetic stem cells,” explains senior author Pier Paolo Pandolfi, MD, PhD, Director of the Cancer Genetics Program in BIDMC’s Cancer Centre and Professor of Medicine and of Pathology at Harvard Medical School. “They are pluripotent, they readily replicate and they can indefinitely remain in a dormant state of quiescence.”
Consequently, while the majority of leukaemic cells are vulnerable to any cancer therapies – including chemotherapy and targeted cancer treatments – that destroy cells during active DNA replication, LICs, 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.
Pandolfi’s laboratory has been working to develop new therapeutic approaches to target LICs and thereby treat chronic myeloid leukaemia (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 tumour suppressor protein that controls fundamental processes such as apoptosis, cellular proliferation and senescence. PML is commonly associated with acute promyelocytic leukaemia (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