By Kenneth Anderson, MD

2008-09-01

Dr. Anderson indicated no relevant conflicts of interest.

Shaffer AL, Emre NC, Lamy L, et al. IRF4 addiction in multiple myeloma. Nature. 2008;454:226-31.

Progress in the treatment of myeloma has directly translated from an improved understanding of the mechanisms of myeloma cell growth, survival, and drug resistance within the bone marrow microenvironment.¹ Specifically, microarray profiling can identify the gene signature of myeloma cells before and after binding of tumor cells to bone marrow stromal cells and show induced changes in tumor as well as stromal cells due to cell-cell contact as well as cytokines. Importantly, targets and targeted therapies within tumor cells and the microenvironment can be validated preclinically in this model (for example, proteasome activity is upregulated in myeloma cells within the bone marrow milieu, and proteasome inhibitors can induce cytotoxicity against myeloma cells by overcoming cell adhesion-mediated drug resistance to conventional therapies).² Excitingly, such targeted therapies can then rapidly translate from the bench to the bedside (for example, proteasome inhibitors have progressed rapidly to FDA approval for treatment of relapsed refractory to relapsed and only recently to newly diagnosed myeloma).^3,4,5 Moreover, combination therapy informed by preclinical studies can also quickly move from the laboratory to the clinic. For example, the demonstration that proteasome inhibitors block DNA damage repair⁶ provided the basis for preclinical and clinical studies showing that proteasome inhibitors can sensitize or overcome resistance to DNA-damaging agents, ultimately culminating in the FDA approval of pegylated liposomal doxorubicin and bortezomib⁷ for treatment of relapsed myeloma.

Genetic knock-down and overexpression studies in myeloma cells now allow for stringent validation of a target as critical for myeloma cell growth.⁸ Shaffer and colleagues have recently carried out elegant small hairpin RNA (shRNA) screening studies, which show that interferon regulatory factor 4 (IRF4) is required for tumor cell viability, and confirmed by the ability of IRF4 overexpression to rescue myeloma cells from lethality induced by IRF4 shRNA. Importantly, there are no intrinsic genetic abnormalities of IRF4 within myeloma cell lines representing the spectrum of known genetic abnormalities in myeloma. Having shown the survival function of IRF4, these investigators utilized gene profiling and genome-wide chromatin analysis to demonstrate IRF4 target genes, such as MYC. Most importantly, IRF4 was also a target of MYC activation, both suggesting that genetic abnormalities of MYC in myeloma can upregulate IRF4 and confirming a MYC-IRF4 autoregulatory growth mechanism in myeloma cells.

These studies both identify hallmark genetic mechanisms underlying myeloma growth and suggest a novel therapeutic target. They demonstrate the power of genetic technologies for functionally validating a target gene and pathway underlying myeloma cell development. Indeed, a novel mechanism of autoregulatory myeloma cell growth has been identified. These studies also provide the basis for genetic mouse models, which may more closely mimic human myeloma. Finally, they identify a novel target and circuit for novel targeted therapies. It would be of interest to see whether any currently available myeloma therapies modulate this pathway. Importantly, it is likely that IRF4 and related circuits are modulated in the bone marrow milieu, and analogous studies in models of myeloma within the tumor microenvironment would further validate both the importance of these findings in myeloma pathogenesis and their potential therapeutic application.

References

1. Hideshima T, Mitsiades C, Tonon G, et al. Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets. Nat Rev Cancer. 2007;7:585-98.
   
   
2. Hideshima T, Richardson P, Chauhan D, et al. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res. 2001;61:3071-6.
   
   
3. Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003;348:2609-17.
   
   
4. Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352:2487-98.
   
   
5. San Miguel J, Schlag R, Khuageva N, et al. Bortezomib plus melphalan-prednisone versus melphalan-prednisone in untreated multiple myeloma patients ineligible for stem cell transplantation. N Engl J Med. 2008. [In press]
   
   
6. Mitsiades N, Mitsiades CS, Poulaki V, et al. Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc Natl Acad Sci USA. 2002;99:14374-9.
   
   
7. Orlowski RZ, Nagler A, Sonneveld P, et al. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol. 2007;25:3892-901.
   
   
8. Carrasco DR, Sukhdeo K, Protopopova M, et al. The differentiation and stress response factor XBP-1 drives multiple myeloma pathogenesis. Cancer Cell. 2007;11:349-60.

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