The CLL mouse

One thing that CLL clears the head about is animal testing. When it comes to finding a cure or control for something that might kill you, touchy-feely considerations go out the window. It is entirely selfish, as well as specie-centric, to put mice through the tortures of laboratories for the benefit of man. It is also an effective way of testing new drugs, figuring out new targets for therapy, and of finding a quicker path to controlling or curing this damned disease.

I come from the background of the guilt-ridden meat eater, the wannabe vegetarian who thinks barbequed pork ribs are extraordinarily tasty and who must stare his own hypocrisy in the face every time he sees his reflection in the glass of the butcher's case. I am, like Homer Simpson, a prisoner of bacon.

I am also convinced that animals have emotions. I have shared my life with cats and have seen it personally. I have no doubt that the same is true of dogs. There is a marvelous book called When Elephants Weep: The Emotional Lives of Animals by Jeffrey Moussaieff Masson. Masson provides compelling evidence that animals do have feelings, "higher" animals at least. (This includes -- shudder -- pigs.) How high are mice on the chain? Not so high that research on mice bothers me sufficiently to oppose it. If it is a matter of them or me, then until the mice rise up and destroy us, I believe using them in cancer research is necessary.

So it is with satisfaction that I read the news that Amy Johnson and the research team at Ohio State University have developed mice with, essentially, CLL. A report in the August 15, 2006 Blood online provides a tantalizing abstract as well as a comment by the renowned CLL expert Dr. John Gribben.

It is worth noting the abstract here, in full, emphasis mine:

"Drug development in human chronic lymphocytic leukemia (CLL) has been limited by lack of a suitable animal model to adequately assess pharmacologic properties relevant to clinical application. A recently described TCL-1 transgenic mouse develops a chronic B-cell CD5+ leukemia that might be useful for such studies. Following confirmation of the natural history of this leukemia in the transgenic mice, we demonstrated that the transformed murine lymphocytes express both relevant therapeutic targets (Bcl-2, Mcl-1, AKT, PDK1, and DNMT1), wild type p53 mutational status, and in vitro sensitivity to therapeutic agents relevant to the treatment of human CLL. We then demonstrated the in vivo clinical activity of low dose fludarabine in transgenic TCL-1 mice with active leukemia. These studies demonstrated both early reduction in blood lymphocyte count and spleen size and prolongation of survival (p=0.046) as compared to control mice. Similar to human CLL, an emergence of resistance was noted with fludarabine treatment in vivo. Overall, these studies suggest that the TCL-1 transgenic leukemia mouse model has similar clinical and therapeutic response properties to human CLL and may therefore serve as a useful in vivo tool to screen new drugs for subsequent development in CLL."

If words aren't enough, the graphics accompanying Gribben's comment include a telling chart showing how the mice developed drug resistance to fludarabine. Fludarabine has gone from the wonder drug to a necessary evil in CLL therapy as doctors have, over time, discovered its negative as well as positive effects. A mouse model such as this may be able to predict drug resistance in a matter of weeks or months -- sparing us human lab rats from having to discover it the hard way over a period of years.

In his comment, Gribben writes:

"While there is naturally great excitement in exploiting strains of mice with leukemia to test therapy, these models will also be invaluable to understand mechanisms of responsiveness and resistance to chemotherapy. Although the initial response rate to fludarabine of patients with CLL is high, eventually patients develop relapse with resistant disease. Here again, Johnson and colleagues have demonstrated the utility of this murine model since these mice demonstrate initial responsiveness to fludarabine in vivo, with resulting modest improvement in survival, but rapidly develop resistant disease. Much work still has to be performed to examine the mechanisms whereby such drug resistance occurs, and in particular whether there is eventual loss of function of p53 as occurs frequently with end-stage CLL. However, this model has sufficient clinical and therapeutic similarities to human CLL to believe that this will open up exciting new opportunities to screen new drugs and novel combinations in vivo and speed therapeutic development in this still incurable disease."

When I saw Dr. John Byrd at Ohio State in June, we discussed fludarabine and disease resistance. While it has been theorized that fludarabine may select for the p53 deletion, killing off all the other CLL clones and allowing the worst one to survive, Byrd emphasized that it has not been proven. Byrd told me that a nine-month study is underway comparing CLL mice receiving fludarabine with CLL mice receiving no treatment. Will the study show a greater incidence of p53 deletions in the fludarabine-treated mice?

Stay tuned. And say a little prayer of thanks for our furry friends with the enlarged spleens and extra-thick necks.