Fighting CLL cells: deciphering the enemy

Comment on Chen et al, page 2513, and comment on Castro et al, page 2506

The last 2 decades have witnessed important progress in the treatment of patients with CLL. Two studies reported in this issue of Blood set the stage for further improvement in the treatment of this common form of leukemia.

Despite important progress in its treatment, chronic lymphocytic leukemia (CLL) remains incurable with conventional therapy. It poses the usual difficulties of treating a disease that affects mainly old people, has a variable prognosis, and for which there is no curative therapy. But as if that was not enough, there is also an increasingly recognized problem in the management of CLL: that is, the presence of neoplastic cells that do not respond to the drugs that form the core of standard treatment of CLL (ie, purine analogs, alkylators). The reasons why a proportion of CLL cells do not respond to otherwise extremely effective agents are complex and far from being completely understood, but mutations of p53, unmutated immunoglobulin heavy-chain variable region (IgVH) genes, and expression of the zeta-associated protein of 70 kDa (ZAP-70) are known factors that correlate with resistance to therapy or a short-lived response to it.

In this issue of Blood, 2 papers provide some important clues on how and why resistance to therapy in CLL might be overcome.

In the first paper, Chen and colleagues from the M. D. Anderson Cancer Center show that flavopiridol (a cyclin-dependent kinase inhibitor) inhibits the phosphorilation of the C-terminal domain (CTD) of RNA polymerase II in CLL cells and reduces RNA synthesis, this being associated with a decline of the transcripts and levels of short-lived antiapoptotic proteins such as myeloid-cell leukemia 1 (Mcl-1). Since Mcl-1 is essential to the increased survival of CLL cells via its antiapoptotic effect, it is not surprising that the decline in Mcl-1 results in cell death. Another important protein contributing to defective apoptosis in CLL, namely B-cell leukemia 2 (Bcl-2), remained unchanged, although its mRNA was consistently reduced. Flavopiridol is already being investigated in clinical trials and has shown promising results.¹ 

In the other paper, Castro and colleagues demonstrate that ZAP-70, which is found in high-risk CLL, expresses activated heat-shock protein 90 (Hsp90). Hsp90 is a molecular chaperone required for the stability and function of multiple mutated, chimeric, and over-expressed signaling proteins that promote cancer-cell growth or survival. Known Hsp “clients” include p53, breakpoint cluster region-abelson (Bcr-Abl), Raf-1, Akt, and human epidermal growth factor receptor 2 (HER2)/Neu (ErbB2), among others.² 

Kipps's group study shows that ZAP-70 should be added to that already long list. Indeed, they nicely demonstrate that ZAP-70–positive cells express Hsp90. In vitro treatment with Hsp90 inhibitors such as 17-allyl-aminogeldanamycin (17-AAG) or 17-dimethyl-aminoethylamino-17-demethoxygeldanamycin (17-DMAG) resulted in degradation and apoptosis of ZAP-70–positive cells, with no effect on ZAP-70–negative cells or T cells. In addition, B-cell–receptor signaling was impaired.

As our understanding of cancer biology unfolds, it is becoming clear that, in the future, treatment of tumors should be individualized based on their genetic diversity. As mentioned, patients with CLL who present p53 mutations do not respond to purine analogs.³  In this regard, the advent of compounds such as flavopiridol, whose mechanism of action does not depend on the p53 pathway, is most welcome. Also, many groups have shown that ZAP-70–positive CLL has poor outcome and often displays resistance to therapy or short-lived responses.^4-6  Hsp90 inhibitors have already shown promising antitumor activity in preclinical model systems and in phase 1 clinical trials,⁷  and they certainly deserve further investigation as potential therapeutic agents for ZAP-70–positive CLL.

The remarkable aspect of the 2 studies highlighted here is that they pave the road for further improvement in the treatment of CLL by revealing important biologic aspects of the disease. Ultimately, as Sun Tzu said in The Art of War, knowing the enemy is a necessary condition to defeat him. ▪