STAT6 in PMBL: pathogenic or passenger?

In this issue of Blood, Ritz and colleagues report that mutations in the transcription factor STAT6 are common events in PMBL.

As the treatment of hematologic cancers evolves from nonspecific cytotoxic drugs to targeted rationally designed therapies, the necessity for identifying key molecular targets becomes increasingly important. Activated kinases, such as Bcr-Abl, Jak2, and Flt3, represent one promising group. However, increasing attention has been directed toward transcription factors, which regulate key cellular processes such as survival, proliferation, and self-renewal. Particular interest has focused on the STAT family of transcription factors, which play a prominent role in mediating the effects of cytokines on hematopoietic cells. The activation of STATs is generally tightly regulated during physiologic signaling. However, mutations affecting the kinases that activate these proteins or the negative regulators that inactivate them can cause constitutive STAT function. This leads to chronic enhanced expression of the genes STATs regulate, which can drive the neoplastic phenotype of hematopoietic cells.

Abundant evidence has pointed to STATs as key mediators of malignancy, as inhibition of STAT function in model systems can lead to a loss of tumorigenicity of cancer cells, and constitutive activation of STATs can be sufficient for neoplastic transformation. STATs can become activated in cancer cells due to autocrine or paracrine activation of cytokine receptors, gain-of-function mutations affecting upstream tyrosine kinases, and loss-of-function mutations in negative regulators including endogenous kinase inhibitors, phosphatases, and proteases.¹ 

One STAT family member, STAT6, plays a particularly important role in lymphocyte biology. It is necessary for Th2 differentiation of T lymphocytes,²  and it promotes the survival and proliferation of B lymphocytes.³  Constitutive activation of STAT6 has been found in primary mediastinal B-cell lymphoma (PMBL),⁴  an uncommon yet aggressive tumor with a predilection for young women, as well as Hodgkin lymphoma, a disease with which it shares certain characteristics.^5,6  STAT6 was known to be activated in several PMBL cell lines and could promote survival of these cells. Since laboratory-generated mutations in STAT6 could lead to its constitutive activation,⁷  Ritz et al in this issue evaluate the hypothesis that mutations in STAT6 might be driving the pathogenesis of PMBL.⁸  In sequencing this gene from 55 PMBL tumors, they found missense mutations in the DNA binding region of STAT6 in 36% of the samples analyzed. By contrast, none of the 25 diffuse large B-cell lymphomas showed mutations in STAT6. DNA derived from nontumor tissue from 2 of the patients with PMBL with mutations in STAT6 did not show these mutations, suggesting that they were acquired during emergence of these lymphomas.

The key question then becomes what do these mutations do to the function of STAT6 in PMBL? The authors tested one such mutant form of STAT6 in model systems and found that it appeared to have diminished function compared with wild-type STAT6. This is somewhat surprising in that STAT6 appears to be functionally activated in PMBL as measured by phosphorylation, nuclear localization, and gene expression. When the expression of 7 STAT6-responsive genes was analyzed, there was no difference between tumors in which STAT6 was mutated from those in which there was no mutation. And so, we are left with a conundrum. The functional activation of STAT6 is very common in PMBL, and mutations in the DNA binding region of the gene are frequently found in this disease. However, it remains unclear whether these point mutations in STAT6 have any direct connection to the pathogenesis of this disease. There are many alternative hypotheses by which these mutations may be functionally important in PMBL. They may affect the expression of other important STAT6 target genes, perhaps by modifying the binding specificity of STAT6, or alter interactions with other transcription factors or coregulators. Perhaps the relative loss of function of the mutant forms of STAT6 is necessary to attenuate the enhanced STAT6 function derived from heightened activity of kinases such as Jak2, or loss of negative regulators such as SOCS1. On the other hand, reflecting the immunoglobulin gene rearrangement that normally occurs in B lymphocytes, B-cell lymphomas often display enhanced somatic hypermutation. It is possible that STAT6 is a particular hotspot for such mutations in PMBL with no functional consequence. Thus, rather than STAT6 mutations being “drivers” of PMBL pathogenesis, perhaps they are “passenger” mutations of little consequence. At this point, only further experimentation will illuminate these possibilities.

Nonetheless, these findings highlight 2 key issues. First, the interchange of ideas between the clinic and the lab exemplified in this work will be essential for the advances we need in elucidating the molecular pathogenesis of cancer. Second, regardless of the function of these newly described STAT6 mutations, evidence continues to grow supporting the key role of transcription factors as mediators of oncogenesis and targets for molecular therapy.