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Teen's leukemia fight inspires father to run

By JESSICA HOPP
Staff Writer

04/10/05 - In the front sitting room of his Belle Meade home, Tom Fouce has a seat on one of two plush white couches. Light from a crystal-laden ceiling fixture brings a brightness to the room that fails to come through the windows on this stormy day.

While he sits, his son, Julian, and wife, Martha, have lunch in another part of the house. Julian, 16, yells something to his mother about having a bowl of cereal. His words echo through the hallways.

It has been four months since Tom started training for the Country Music Half-Marathon with Team in Training an organization that helps raise money for The Leukemia and Lymphoma Society.

It has been six years since Julian was diagnosed with acute lymphocytic leukemia, a cancer that prevents bone marrow from producing normal red blood cells, white blood cells and platelets.

As silverware and plates clank in a distant room, Tom talks about his son's diagnosis, his decision to run, and his hopes for April 30 the day of the race.

He begins with the diagnosis.

It was a cut on Julian's cracked, dry, winter-weather lips that alerted the Fouce family to Julian's situation. When the cut continually failed to heal, Julian was taken to a doctor and underwent tests. His body was not producing the healing platelets like it should be. Julian was diagnosed with leukemia it was just a few days before his 10th birthday.

''My first reaction was just numbness,'' Tom Fouce said. ''You just deal with it. You keep your head down, and you keep going forward. You can't, or at least I can't, wallow in self-pity. It is what it is. I don't know why he got sick, and I don't know why people get leukemia, but he did and you have to deal with it.''

Julian's first chemotherapy treatments came on his 10th birthday. He went into remission twice over the next few years, but each time the cancer came back. Most recently, it returned in August.

At that time it was decided that Julian would undergo a bone marrow transplant. A donor drive was held by Vanderbilt Hospital in Julian's honor in October, and the procedure was set to take place, but there was a setback.

Julian developed a lung infection and had to have surgery on his right lung before the transplant.

It was around that time that Tom made his decision to run. It was a spur of the moment choice.

Coming home from the hospital one day, Tom and Julian stopped at the Athlete's House, a Nashville athletic store, to buy some new shoes for Julian. The fitting process took some time, and while he was waiting Tom glanced over brochures and pamphlets. There, a flier about an upcoming Team in Training meeting regarding the marathon and half-marathon caught his eye.

It was Thursday. The meeting was Saturday. He decided to attend.

''It never occurred to me before to run a marathon,'' Tom said. ''Not even now that I know that I can run a half marathon, because I have done the distance. I imagine I could run a marathon, but I don't know why I would want to. So it's not like this passion for running. I wouldn't have signed up to run just to do the half marathon without having it be Team in Training.''

Each runner who joins Team in Training is expected to raise a specified amount of money for the cause. The amount is determined by the type of event and its location. For people in Nashville who are running the half-marathon there is a fundraising goal of $1,700. So far Tom has raised more than $20,000.

''It has just been really overwhelming,'' Tom Fouce said. ''I really didn't know what to expect, but people have said, 'Thank you for letting me participate.' ''

''Everybody wants to do something. They say, 'What can we do to help?' I tell them, 'Pray, chant, have good thoughts, whatever it is you do, do it,' but there really isn't anything that you can do. So this gives people a chance to feel like they are doing something.''

And for the Fouce family, it means more knowing the money will go toward helping people like Julian.

''It has even more impact now for us,'' Maria Fouce said. ''This time around, with the relapse situation, there is really no set protocol and it really just gets that much harder.''

Right now, Julian's February bone marrow transplant is looking successful. Julian's own DNA, which has been producing cancerous blood cells, has been replaced by his donor's DNA and healthy cells are being made.

However, Tom said, the cells are not reproducing at a rate the doctors would like. There is a possibility they could go back to the donor and ask for more cells, but Tom said he is unsure where they will go from here.

One thing he does know is, although Julian is still fatigued and in need of care, he no longer has leukemia.

Tom will continue to take whatever steps necessary to help ensure his son's health. His next step will be toward the finish line at the end of April. His hope is that Julian will be well enough to meet him there.

Jessica Hopp is a staff writer for The Tennessean. Reach her at 259-8253 or [email protected].

St. Jude Unlocks Mystery of Very Aggressive Leukemia

Acute lymphoblastic leukemia

St. Jude Children's Research Hospital - Apr 19 2006 - Investigators at St. Jude Children's Research Hospital have used mouse models to determine why some forms of acute lymphoblastic leukemia (ALL) are extremely aggressive and resist a drug that is effective in treating a different type of leukemia.

The investigators found that the combination of a mutation called Bcr-Abl and the loss of both copies of the tumor suppressor gene Arf in bone marrow cells triggers an aggressive form of acute lymphoblastic leukemia. Inactivation of both Arf genes facilitated the multiplication of leukemic cells that did not respond to the drug imatinib (Gleevec®). Imatinib is already successfully used to treat chronic myelogenous leukemia (CML), another blood cell cancer caused by the Bcr-Abl mutation.

The St. Jude study provided evidence that imatinib resistance in mouse models of acute lymphoblastic leukemia did not depend strictly on the presence of Bcr-Abl and the loss of Arf genes in the cancer cells themselves. Rather, drug resistance reflected an interaction of the tumor cells with specific growth-promoting factors produced in the mice. After removal of leukemic cells from mice that had failed imatinib therapy, compounds inhibiting enzymes called JAK kinases restored the cells' imatinib sensitivity.

The study's findings suggest why imatinib may fail to cause remission of acute lymphoblastic leukemia in patients with the Bcr-Abl mutation and point to a strategy for overcoming this resistance. A report on this work appears in the April 17 issue of Proceedings of the National Academy of Sciences.

The Bcr-Abl oncogene (a cancer-causing gene) is formed when parts of two chromosomes switch places, leading to fusion of a fragment of the Bcr gene from one chromosome to a portion of the Abl gene from the other. Bcr-Abl encodes a type of enzyme called a tyrosine kinase, which then drives the abnormal, uncontrolled multiplication of leukemic cells.

Other researchers had previously shown that inhibiting the Bcr-Abl kinase with imatinib causes durable remissions of cancer with minimal side effects in patients with CML--a finding that has revolutionized the treatment of this form of leukemia. However, imatinib has proven far less effective in treating acute lymphoblastic leukemia patients with the Bcr-Abl mutation, and the basis of drug resistance in this disease is unknown.

The Arf gene normally suppresses the proliferation of cells carrying cancer-causing mutations such as Bcr-Abl, according to Charles J. Sherr, M.D., Ph.D., a Howard Hughes Medical Institute investigator and co-chair of the St. Jude Department of Genetics and Tumor Cell Biology. Arf acts as a safeguard against the cancer-causing effects of Bcr-Abl, Sherr said. Sherr is senior author of the paper. The Arf gene was discovered at St. Jude in 1995 in the laboratory of Sherr and Martine F. Roussel, Ph.D., a member of the Department of Genetics and Tumor Cell Biology. Roussel is also an author of the current paper.

The St. Jude team found that Arf is not inactivated in CML patients who respond to imatinib. This is in contrast to acute lymphoblastic leukemia, in which Arf loss frequently occurs and imatinib treatment is far less effective. "This suggested to us that inactivation of Arf in ALL cells expressing the Bcr-Abl enzyme gives these cells a strong proliferative (cell multiplication) advantage," Sherr said. "And this advantage might contribute to imatinib resistance in some way."

To investigate this hypothesis, the researchers used a virus-like piece of DNA to carry the Bcr-Abl oncogene into bone marrow-derived lymphocytes obtained from mice that either retained Arf or were previously engineered to lack this gene. These pre-B lymphocytes represent one type of white blood cell that can become cancerous and cause acute lymphoblastic leukemia.

The researchers then transplanted these "transformed" cells carrying Bcr-Abl back into normal mice. Animals that received transformed pre-B cells that had both copies of the Arf gene intact were highly resistant to disease development. However, mice injected with cells that carried Bcr-Abl and lacked Arf rapidly developed an aggressive form of ALL that could not be cured with high doses of imatinib.

"Intriguingly, tumor cells removed from these resistant mice and treated with imatinib in cell cultures were still very sensitive to this drug," noted Richard T. Williams, M.D., Ph.D., a fellow in Sherr's laboratory and the paper's lead author. "This suggested to us that the failure of imatinib to cure the mice depended on some substance in the animal that stimulated tumor cell replication or survival."

Sherr's team guessed that one such factor might be the B lymphocyte stimulating protein IL-7. Normally produced in the bone marrow, IL-7 further enhanced the proliferation of cultured leukemic cells removed from the mice and made the cells resistant to imatinib's growth inhibitory effects.

IL-7 binds to receptors on the surface of lymphocytes, which triggers the activity of the JAK kinases. The activated JAK kinases then stimulate cell growth through a signaling pathway that operates alongside the one controlled by the Bcr-Abl kinase, Sherr said. Therefore, the St. Jude investigators used a chemical inhibitor of JAK kinases to block the effect of IL-7 on leukemic cells in culture. This treatment restored the acute lymphoblastic leukemia cells' sensitivity to imatinib.

"Our study of mice with ALL containing both Bcr-Abl and Arf mutations has provided unexpected insights into how factors in the mice - and potentially in humans - might contribute to imatinib resistance," Williams said. "Although our efforts to block IL-7 were limited to cell cultures, our mouse model provides an inexpensive and efficient way to test newly developed JAK kinase inhibitors and other drugs."

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