The identity crisis of Krüppel-like factor 4

Non-Hodgkin lymphoma (NHL) is the fifth most common childhood cancer, with 10–20 cases diagnosed per million people each year [1]. The most common subtypes of NHL in children arise from B cell progenitors, and include Burkitt lymphoma, diffuse large B-cell lymphoma and B lymphoblastic lymphoma. In children these lymphomas tend to be aggressive, requiring intense multiagent chemotherapy regimens to achieve cures, and while survival rates for children diagnosed with NHL are excellent, 20% still die from disease [1,2]. Disease features, such as clinical stage and serum lactate dehydrogenase at diagnosis, have been identified to assist in risk stratification of patients [3], but in an era of increasingly targeted therapy to improve outcomes of higher risk groups, an understanding of the molecular drivers of malignancies is increasingly important.

In this issue of Leukemia and Lymphoma, Valencia-Hipolito et al. report their findings of increased expression of Krüppel-like factor 4 (KLF4) in several B-NHL cell lines, as well as in tumor samples from 100 pediatric patients with B-NHL [4]. The authors also found an association between increased KLF4 expression and poor survival, especially in those patients with Burkitt lymphoma. In a disease with a greater than 80% survival rate, even for those with classically categorized “high-risk” disease, fewer than 25% of those patients with increased expression of KLF4 survived. The finding of a new prognostic factor with the potential to identify more at-risk patients is appealing. Using cytogenetic and molecular markers has allowed the development of risk-based therapy and improved outcomes in a number of childhood cancers: acute lymphoblastic leukemia, acute myeloid leukemia and neuroblastoma, to name a few. By comparison, our risk-stratification for NHL is in the early stages of its evolution, and even though outcomes have improved significantly, it has not been without an increase in toxicity, especially myelosuppression and mucositis, as our treatment regimens have become progressively more intense. Despite improvements in overall outcomes, for patients with stage IV disease or those who have relapsed, outcomes remain quite poor [5,6]. Of utmost importance, therefore, is the identification of proteins whose expression levels are not only prognostic, but also may provide insight into the underlying tumor biology.

Studies of KLF4 in other cancers, including breast cancer and squamous cell carcinoma, support its role as an oncogene. Alternatively, KLF4 has been identified as a tumor suppressor in other cancers, namely those of the gastrointestinal tract. It is not only KLF4 that appears to have a split personality – transforming growth factor-β (TGF-β), NOTCH and RUNX have all been found to function both as tumor suppressors and as oncogenes, depending on their setting [7].

KLF4 is a zinc-finger transcriptional regulator that is involved in a wide variety of cellular processes, including differentiation, proliferation and apoptosis. These seemingly contradictory roles as both tumor suppressor and oncogene support the presence of modifying factors that influence the ability of KLF4 to induce differentiation or proliferation. In fact there is evidence that the opposing functions of KLF4 may be related to an interaction between it and the tumor suppressor p53 [8]. Furthermore, this interaction likely involves the Ras–cyclin D pathway and p21, which itself has been shown to have both tumor suppressor and oncogenic properties [8]. Perhaps most interesting in the context of Burkitt lymphoma is that in several systems both the KLF4 and MYC oncogenes have been shown to function similarly, but in others have been demonstrated to be oppositional [7]. Taken together, this underscores the complexity of the biological processes that drive tumorigenesis. Increasingly targeted therapy offers improved outcomes for patients, often with better toxicity profiles compared to classic cytotoxic chemotherapeutic agents. However, an understanding of the precise roles that targeted proteins play is imperative, especially when that role may vary depending on the tumor type.

Recognition of KLF4 as a prognostic factor in Burkitt lymphoma may allow us to identify subgroups of patients with more aggressive disease. In turn, intensifying therapy for these patients may improve their disease-free outcomes, but this must be done without untoward toxicities. Identification of pathways involved in tumor development is appealing due to the promise of targeted therapy. However, as the growing body of tumor biology literature demonstrates, it is clear that the role of many proteins involved is complex, and at times entirely unclear.

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