Researchers at King’s College London have discovered that leukemic stem cells can be reversed to a pre-leukemic stage by suppressing a protein called beta-catenin found in the blood.
They also found that advanced leukemic stem cells that had become resistant to treatment could be ‘re-sensitized’ to treatment by suppressing the same protein.
Professor Eric So (pictured), who led the study at the Department of Hematology at King’s College London, says the findings represent a ‘critical step forward’ in the search for more effective treatments for aggressive forms of leukemia.
The role that beta-catenin plays in the development and drug-resistance of stem cells in acute leukemia was previously unknown. This study reveals its significance and highlights it as a potential therapeutic target that could allow selective eradication of leukemic stem cells.
King’s scientists looked at leukemic stem cells found in types of leukemia that involve mutations of the MLL gene. This accounts for around 70 per cent of infant leukemias and 10 per cent of adult acute leukemias. The prognosis for this type of leukemia in children is not good – only 50 per cent survive past 2 years after receiving standard anti-leukemia treatment.
To understand how the disease develops, the King’s team carried out a series of experiments to look at how pre-leukemic stem cells (which do not always develop into leukemia) are different to leukemic stem cells, which sustain the disease and are likely to be responsible for relapse. They carried out studies in mice, in cultured human cells derived from cord blood, and on human leukemic cells obtained from two leukemia patients.
The studies in mice showed that pre-leukemic cells developed into leukemic stem cells and induced leukemia, in part by activation of beta-catenin. But suppression of beta-catenin in leukemic stem cells reduced leukemic cell growth, delayed the onset of leukemia and reversed the stem cells to a pre-leukemic stage. Furthermore, when beta-catenin was completely inactivated in mice with pre-leukemic cells, the mice did not develop leukemia, even though they carried MLL gene mutations.
Researchers then wanted to see how suppression of the beta-catenin protein impaired human leukemic cells. They found that suppression of the protein in MLL leukemic cells again diminished their ability to proliferate and renew themselves (an essential part of how leukemia develops). This confirmed the important role of beta-catenin in the human disease.
The study also revealed a previously unrecognized critical function of beta-catenin in mediating drug resistant properties of leukemic stem cells. Leukemic stem cells can become resistant to treatment in some cases but, crucially, this study showed that suppression of beta-catenin in human MLL leukemic cells made them sensitive again.
Professor Eric So, who led the study at King’s, said, “These results are extremely exciting and represent a critical step forward in the search for more effective treatments for this devastating form of leukemia. The findings provide compelling evidence that this protein could be exploited to develop an effective therapeutic target for this form of the disease.”
“Most of the current anti-cancer therapies used to treat leukemia attack healthy blood cells as well as cancerous ones. Interestingly, beta-catenin is not required for normal blood stem cells. So if we can specifically target beta-catenin in the bone marrow, we can have potentially a more effective and less toxic anti-leukemia therapy that can efficiently eradicate leukemic stem cells but spares healthy blood stem cells.”
“Much more research needs to be done before we can adopt this approach in treating people with leukemia, but the findings of this study do look promising. We will now investigate the mechanisms behind these molecular changes to find out why beta-catenin is so important in the development of MLL leukemia, and if we can apply the principle to other types of leukemia.”
Dr Mark Matfield, AICR's scientific coordinator said, “The whole field of cancer stem cell research is relatively new, but this discovery has the potential to be one of the most useful in this rapidly-advancing area, because it shows us directly how a new treatment could be developed.”
Illustration: Eric So Research Lab.
King’s College London News (12/13/10)
Abstract (Cancer Cell, Volume 18, Issue 6, 606-618, 14 December 2010)