|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
Blood, 30 April 2009, Vol. 113, No. 18, pp. 4132-4133.
Hiding from ABT-737 in lymph nodesDANA-FARBER CANCER INSTITUTE
CLL cells almost universally express high amounts of the antiapoptotic protein BCL-2 and appear to be addicted to this expression; therefore, CLL has become a testing ground for BCL-2 antagonists. In this issue of Blood, Vogler and colleagues show that response of CLL to the BCL-2 antagonist ABT-737 critically depends on the microenvironment. They demonstrate that the explanation lies in increased expression of antiapoptotic proteins with implications for response to many kinds of CLL therapy.
In this issue of Blood, Vogler et al ask whether the microenvironment of CLL cells might affect their sensitivity to ABT-737.3 It has previously been noted that occupation of the lymph node niche and concomitant signaling by stromal cells seems to afford resistance to conventional chemotherapeutic agents in CLL.4 Certainly, it is a common clinical observation that patients with high circulating lymphocyte counts can be treated with a dramatic reduction in counts, only to subsequently relapse primarily in lymph nodes with a much lower peripheral blood white cell count. In this paper, Vogler et al mimic occupation of the lymph node niche by coculture with fibroblasts expressing CD154 in the presence of IL-4. They find that in this coculture 1000-fold greater concentrations of ABT-737 are required to kill CLL cells. When they looked for changes in expression of BCL-2 family proteins, they replicated prior results that found that levels of BFL-1/A1 and BCL-XL protein were dramatically increased.5 Because BFL-1/A1 is poorly targeted by ABT-737, it is suggested that it is available to bind the proapoptotic molecules displaced by ABT-737 for BCL-2. BCL-XL might do the same. In addition, newly synthesized BCL-XL, relatively unoccupied by prodeath proteins, might also act as a sink for intracellular ABT-737, decreasing the concentration of drug available to antagonize BCL-2. Reducing expression of both of these proteins by siRNA restored sensitivity to levels comparable to circulating cells cultured in the absence of fibroblasts. In addition, treatment with the drugs seliciclib and TSA, which lower BFL-1/A1 levels, also increases the sensitivity of cocultured CLL cells to ABT-737. Though apparently effective, these latter drug combinations must be interpreted with some caution, as they do not purely act through the decrease of BFL-1/A1 levels. This work provokes concrete predictions. First, the amount of BCL-XL and BFL-1/A1 is predicted to be much higher in CD5+ CD23+ lymphocytes derived from the lymph nodes of CLL patients compared with those isolated from the circulation. Second, in clinical trials of ABT-263, an orally available derivative of ABT-737, one would predict a more consistent response in decreasing circulating lymphocyte counts than in shrinking nodal disease. Third, one would predict, as the authors do, that drugs that could simultaneously target all antiapoptotic BCL-2 family proteins, including MCL-1 and BFL-1/A1 might be more effective for CLL. Doubtless, such agents would be more toxic to CLL cells. The question remains: Would such agents provide a wider therapeutic window, or would they be too toxic to normal tissues? Conventional agents used in CLL treatment, including alkylating agents, fludarabine, and rituximab, can kill CLL cells via the mitochondrial apoptotic pathway. Increased BCL-XL and BFL-1/A1 would therefore be expected to cause resistance to apoptosis induced by these conventional agents. These results suggest that strategies to drive CLL cells from their lymph node niches might be an important prerequisite for killing them, not only by BCL-2 antagonists, but by conventional agents as well. Little is known about the equilibrium between the circulating state and the lymph node resident state in CLL, but the results of Vogler et al suggest that this may be a critically important area of study to improve CLL treatment.
Footnotes
Conflict-of-interest disclosure: A.L. is cofounder of Eutropics Pharmaceuticals.
REFERENCES
  CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
Related Articles in Blood Online:
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|||||||
 |
 |
 |
 |
 |
 |
 |
 |
||
| Copyright © 2009 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
