How to Stop Leukemia from Returning? Block β-catenin Pathway

Target stem cells to prevent leukemia’s return, Harvard scientists say. Usually, stem cells are seen as the “good guys,” and today, research into their regenerative properties is at an all time high. As the “building blocks” of the body that can go on to develop into blood, bone, brain and body organ tissues — they are seen as a potential renewable source of replacement tissues to treat many ailments for which there is no cure, or for which few treatments exist.

But where leukemia is concerned, stem cells are both the “good” and the “bad” guys. As the “good guys,” they are used in the bone marrow transplantation to treat this blood cancer.

But they are also the “bad guys” — leukemic stem cells are the very things that sustain this blood-forming disease, which affects about 245,000 Americans, and an additional 47,150 new cases that are expected to develop this year alone. Leukemic stem cells are also thought to be responsible for relapse — and 23,540 Americans are expected to die from the disease this year, according to the National Cancer Institute.

Thus, the eradication of these type of stem cells is believed to be the key to achieving the complete remission of leukemia.

Leukemia causes the blood-forming tissue in the bone marrow to produce large numbers of white blood that enter the bloodstream — crowding out normal blood cells and leading to anemia, bleeding and infections. Often, leukemia also spreads to the lymph nodes or other organs, causing swelling and pain.

Chronic myelogenous leukemia or chronic myeloid leukemia (CML) is one of four types of leukemias that progresses slowly and occurs mostly in children and in middle-aged adults.

In the case of 11-year old American, C.J. Banaszek, CML started with a nosebleed that lasted too long, prompting his mother to rush her son to the nearby Petaluma Valley Hospital, where he was diagnosed with CML in the early hours of Feb. 21.

His mom’s search for a bone marrow donor to match C.J.’s blood type has prompted her to embark on a mission to raise awareness about the importance — and relative ease — of donating bone marrow. This mission landed her and her son on the pages of the San Francisco Chronicle last April 7.

Meanwhile, C.J. has been out of school while he takes oral chemotherapy. He keeps busy reading, writing and constructing Lego sets at his Petaluma, California home while he waits to find a bone marrow match — his family believes that a bone marrow transplant is the only thing that will cure C.J.

Leukemia stem cells cause cancer to return
A pill called imatinib — known by its brand name Gleevec — is the first treatment for everyone with CML.
Sometimes, a chemotherapy medicine called hydroxyurea — marketed as Hydrea — is used temporarily to reduce the white blood cell count if it is very high at diagnosis.

The vast majority of CML patients taking drugs like imatinib go into remission — but often their cancer returns because lingering leukemia stem cells stubbornly resist these existing therapies.

New findings from Harvard researchers suggest that a combination approach to therapy is more effective and may stamp out CML for good. The researchers make their conclusions based on findings of their experiment on lab mice and publish these in the April issue of Cell Stem Cell.

“Imatinib inhibits the oncoprotein — that drives CML — and it is incredibly effective at putting patients into remission,” says Dr. Scott Armstrong, a prominent oncologist and hematologist who is co-director of the Harvard Stem Cell Institute Cancer Program and co-director of the leukemia program in the Dana-Farber Harvard Cancer Center. “But there is growing evidence that this doesn’t rid the body of the most immature cancer cells. The question is: How can we eradicate those cells?”

Focusing on the β-catenin pathway
Dr. Armstrong and his colleagues focused on the so-called β-catenin pathway — a pathway known to be important in blood stem cells during their early development but not in adulthood.

What the researchers found in their study on mice was that leukemia stem cells revert back to their dependence on this β-catenin pathway, leaving them vulnerable to treatments aimed at this pathway.

As expected, when the researchers gave β-catenin inhibitors to the mice, this helped eliminate leukemia stem cells — as did a pain-relieving drug already in use that lowers β-catenin levels indirectly. What this suggests is that combining imatinib with β-catenin inhibitors can help to prevent the recurrence of the blood cancer.

Even better, the β-catenin blockers got rid of leukemia and its stem cells once and for all in lab mice, but left the healthy blood stem cells unscathed.

“The appeal is that this pathway is important for the leukemia, but not for normal cells,” Dr. Armstrong says. “It gives us an angle for therapy.”

But more work has to be done to ensure that β-catenin blockers work just as well in people as they do in mice, Dr. Armstrong cautions. And if these blockers do, CML patients aren’t the only ones who will benefit from the new treatment strategy — these blockers may also be used for harder-to-treat forms of cancer, and to treat patients who have entered the acute stage of CML or those who suffer from colon cancer.

Other authors also associated with the Harvard Stem Cell Institute Cancer Program and the Dana-Farber Harvard Cancer Center as well as the Children’s Hospital in Boston, and two German cancer institutes — one at the University Hospital of Otto-von-Guericke University and another at the University Hospital Ulm, as well as the Queensland Institute for Medical Research in Australia are Dr. Florian H. Heidel, Dr. Lars Bullinger, Dr. Zhaohui Feng, Dr. Zhu Wang, Dr. Tobias A. Neff, Dr. Lauren Stein, Dr. Demetrios Kalaitzidis and Dr. Steven W. Lane.

London researchers come to the same conclusion
But Dr. Armstrong’s team wasn’t the first to identify the role of the β-catenin pathway in the progression and drug-resistance of leukemia stem cells. The credit goes to a team of British scientists at the King’s College London led by Dr. Eric So. This team was the first to identify the role the β-catenin proteins play in the blood cancer — but in a more aggressive form caused by mutations of the MLL gene.

Writing on December 13, 2010 in the journal Cancer Cell, Dr. So’s team also concluded that leukemic stem cells can be reversed to a pre-leukemic stage by suppressing the β-catenins. The King’s College researchers also found that advanced leukemic stem cells that had become resistant to treatment could be “re-sensitized” to treatment by suppressing the same protein. They had also been doing early work on lab mice.

Even better, the British scientists were investigating leukemic stem cells found in the more aggressive form of leukemia — which accounts for 70 percent of infant leukemias and one in ten of adult leukemias. In infants, the prognosis for this type of leukemia isn’t good — only half survive past two years after receiving standard anti-leukemia treatment.

The gravity and aggressiveness of this form of leukemia only highlights the significance of the findings from Dr. So’s team.

“Most of the current anti-cancer therapies used to treat leukemia attack healthy blood cells as well as cancerous ones,” Dr. So notes. “Interestingly, β-catenin is not required for normal blood stem cells. So if we can specifically target β-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 spare healthy blood stem cells,” he said — and his thoughts are echoed more recently by Harvard’s Dr. Armstrong.

“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,” he said.

The King’s college researchers have since gone on to investigate the mechanisms behind these molecular changes in a bid to find out why β-catenin is so important in the development of MLL leukemia.