Check the brakes on IRF4! Free

In this issue of Blood, Chakraborty et al¹ uncover a novel mechanism of control of the transcription factor IRF4. They show that BCL7A can act as a tumor suppressor by interacting with IRF4, impairing IRF4’s ability to bind DNA and orchestrate its usual downstream transcriptional program. Loss of BCL7A therefore allows IRF4 activity to proceed unchecked, driving myeloma-cell proliferation.

IRF4 is a transcription factor with an oncogenic role in several malignancies. In myeloma it has long been recognized as an addiction and thus a potential “Achilles’ heel”^2,3 as IRF4 drives a different transcriptional network in myeloma cells to that in normal plasma cells or B cells at other stages of differentiation. It is one of the most significant dependencies in myeloma and the ultimate target of the highly effective immunomodulatory agent (IMiD) class of antimyeloma treatment. IMiDs, which downregulate IRF4 through degradation of its key transcription factors Ikaros and Aiolos via the E3-ligase CRBN, are a cornerstone of myeloma therapy, but resistance to treatment eventually arises due to mechanisms including downregulation or mutation of CRBN⁴ and transcriptional plasticity.^5,6 Further understanding how IRF4 activity is controlled is therefore critical to identifying alternative approaches to target this pathway.

Using whole-genome sequencing and RNA sequencing, Chakraborty et al identified very frequent mutations in the 5′ untranslated region of BCL7A (seen in 62% of patients with myeloma) and reported that BCL7A RNA expression is lower than in normal plasma cells. Extensive subsequent functional experiments characterized the effect of loss of BCL7A in cell lines and in vivo models, showing that loss of BCL7A increased proliferation, reduced mitochondrial metabolism and reactive oxygen species levels, and increased expression of IRF4-associated cytokines. The reverse was also demonstrated with induced overexpression of BCL7A, that is, reducing proliferation in cell lines with lack of constitutive expression. There was no increase in protein expression of IRF4 itself with loss of BCL7A, but direct binding between IRF4 and BCL7A was demonstrated with an associated lack of IRF4 binding to its target sequence, suggesting BCL7A can directly sequester IRF4, thereby preventing its transcriptional activity.

Of note, in the current study the presence of BCL7A mutation was not directly correlated with lower RNA expression, suggesting that additional mechanisms may also be involved in downregulation. In contrast, a previous study had reported an association between BCL7A mutation and expression along with differences in patients from different racial backgrounds.⁷ The latter was unfortunately not possible to examine in the current analysis due to lack of available data but would be of interest to explore further in future studies. Irrespectively, a clear reduction in expression of BCL7A is demonstrated and was almost universal across samples. Interestingly, BCL7A mutation and low expression were identified even in the precursor conditions to myeloma, suggesting they occur as an early event in myeloma pathogenesis and therefore require cooperativity with additional events to drive malignant transformation to the later stages of disease.

Novel approaches to targeting IRF4 therapeutically, aside from IMiDs, have largely focused on other regulators such as EP300/CBP⁸ or SWI/SNF.⁹ As a transcription factor, direct targeting of IRF4 therapeutically has proved challenging to date, but novel approaches such as protein degradation¹⁰ will perhaps be able to overcome this hurdle. Importantly, any approach targeting IRF4 as a myeloma therapeutic has the potential benefit of having a therapeutic window for activity between myeloma and normal plasma cells, hopefully sparing some of the side effects such as significant immunosuppression associated with hypogammaglobulinemia seen when this myeloma specificity is not present. Further studies to understand the site of interaction between BCL7A and IRF4 that leads to its sequestration and inactivation uncovered by Chakraborty et al may perhaps enhance proximity-inducing therapeutic efforts or open alternative therapeutic avenues.

In summary, this work elegantly describes how BCL7A downregulation “releases the brakes” on IRF4, contributing to myeloma cell “acceleration.”

Conflict-of-interest disclosure: C.P. has received honoraria from Celgene/Bristol Myers Squibb for advisory boards, educational talks, and participation in data monitoring boards; from Janssen, GlaxoSmithKline, and Sanofi for advisory boards and educational talks; from Pfizer, iTEOS Therapeutics, and Opna Bio for advisory boards; and from AbbVie and Amgen for educational talks.