Leukemia Awareness

Researchers have discovered that by enriching a class of blood stem cells they can inhibit the growth of a rare but aggressive form of leukemia.

Dr. Yaacov Ben-David, a senior scientist at Sunnybrook Research Institute, and colleagues found that the presence of leukemic inhibitory stem cells in the spleens of a mouse model slows the advance of erythroleukemia, a cancer in which a large number of abnormal red blood cells grow in the blood and bone marrow. Prognosis for patients with this type of leukemia is poor.

With this discovery, scientists have a new model for the development of a more efficient drug therapy for this and other forms of leukemia. It also suggests a route for a novel combination therapy, one that targets both genes and cells.

“Many scientists are using targeted therapy for genes that activate or control the growth of cancer cells,” says Ben-David, who is also a professor at the University of Toronto. “But the cellular environment around the tumour, its microenvironment, is the body’s first defence. If we can first strengthen it by the enrichment of inhibitory stem cells, then we may have a better treatment for patients than with targeted therapy alone.”

For their study, the researchers turned to a mouse model of a noncancerous blood disorder, in which the bone marrow makes too many red blood cells. With this condition, despite having an abnormally high number of blood cells, these mice rarely develop erythroleukemia. The researchers thus hypothesized that the inhibitory stem cells have a protective effect. To test their hypothesis, the scientists induced erythroleukemia in mouse models with this noncancerous blood disorder. Upon analysis, they found that the ability of the leukemic inhibitory stem cells to secrete nitric oxide was primarily responsible for the cells’ anti-tumour properties. They also discovered that specific cytokines, signalling molecules that tell cells how to communicate with each other, enriched the stem cells, strengthening the anti-tumour effect.

“I’m very excited about this work,” says Ben-David, whose lab was the first to show, in 2004, that two proteins in the micro-environment of the spleen hasten the growth of leukemic cells, and that removal of the spleen might therefore be a way to halt the spread of leukemia, an approach now being clinically tested at Sunnybrook. Now that we’ve identified a molecular mechanism preclinically, we can look at performing a clinical trial in the near future,” he says.

Erythroleukemia typically affects people aged over 50 years old, though it affects all age groups, including children, and more men than women get it. Risk factors include prior exposure to chemicals, including chemotherapy to treat cancer. (research was supported by the Canadian Institutes of Health Research).

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New targeted therapy finds and eliminates deadly leukemia stem cells

New research describes a molecular tool that shows great promise as a therapeutic for human acute myeloid leukemia (AML), a notoriously treatment-resistant blood cancer. The study, published by Cell Press in the July 2nd issue of the journal Cell Stem Cell, describes exciting preclinical studies in which a new therapeutic approach selectively attacks human cancer cells grown in the lab and in animal models of leukemia.

According to a press release issued by EurekAlert, AML is a cancer of the white blood cells that has an extremely poor prognosis and does not respond well to conventional chemotherapy. “The cellular and molecular basis for this dismal picture is unclear,” offers senior study author Associate Professor Richard Lock from the Children’s Cancer Institute Australia and the University of New South Wales. “However, previous research has suggested that leukemia stem cells (LSCs) may lie at the heart of post-treatment relapse and chemoresistance.” LSCs are cells that can initiate AML and are critical for its long-term growth.

Associate Professor Lock and colleagues exploited the fact that the molecule CD123 is expressed at very high levels on LSCs but not on normal blood cells. CD123 is part of the interleukin-3 receptor, a protein that interacts with a growth factor (called a cytokine) that influences cell survival and proliferation. The researchers created a therapeutic antibody that recognized and bound to CD123 with the hope that this antibody would selectively interfere with AML-LSC survival.

When AML-LSCs from human patients were transplanted into mice treated with the antibody, called 7G3, cytokine signaling in the tumor cells was blocked. Further, 7G3 impaired migration of the AML-LSCs to bone marrow and activated the innate immune system of the host mouse to destroy the AML-LSCs. Overall, treatment with 7G3 substantially improved mouse survival when compared with control groups. The researchers go on to report that a CD123-targeting antibody is currently being used in phase 1 clinical trials of advanced AML and that there are no signs of treatment-related toxicity.

These results hold substantial promise for future cancer therapeutics. “The recent characterization of defined populations of cancer stem cells in a range of human malignancies, as well as their relative resistance to conventional chemotherapy and radiotherapy, supports the broad applicability of our approach and provides rationale for the progression of AML-LSC-targeted therapeutics from preclinical evaluation to clinical trials,” concludes Associate Professor Lock. (as reported by “The Hindu”)