Target JunB to tackle myeloma

August 7, 2021 0 By FM

Aresearch team led by physicians of the Karl Landsteiner University of Health Sciences in Krems has identified a potential drug target to treat multiple myeloma (MM) by uncovering a pivotal role for a regulator protein.

A transcription factor (TF) known as JunB plays central in MM pathogenesis as it significantly influences the development of tumour-inducing blood vessels in the bone marrow (BM) of the patients suffering from blood cancer, established the researchers using a series of different experiments.

“This makes JunB a promising therapeutic target. Its inhibition may even prevent the initiation of symptomatic MM,” says Dr Klaus Podar, Head of the Multiple Myeloma Programme, Department of Internal Medicine II at Krems University Hospital, who led the study.

The results add another facet of JunB to the pathophysiologic functions in MM and underscore worldwide efforts to directly target TFs such as JunB as one of the most promising future strategies in cancer, and in MM therapy in particular, he adds.

MM is the second most common form of cancer in haematopoietic cells. Despite significant therapeutic advances over the past two decades, MM remains incurable. A critical factor in MM pathogenesis is the formation of new blood vessels in the bone marrow. The exact molecular mechanisms leading to this process are still unknown.

Independent of hypoxia

Importantly, the results also demonstrated that JunB function was independent of low oxygen levels in the tumour microenvironment – usually a crucial factor for the production of pro-angiogenic factors.

“Indeed, hypoxia and the angiogenic master regulator Hif-1α levels increase in the BM of MM patients during disease progression due to rapidly proliferating tumour cells and promote MM cell dissemination,’’ remarks Dr Podar, who is also Head of Working Group “Molecular Oncology/Hematology”.

The results, however, demonstrate that JunB and Hif-1α expression levels are functionally regulated by distinct features within the BM microenvironment, the cellular compartment and liquid milieu, and hypoxia, respectively.

The research team surmises that MM cells, in which JunB is upregulated, rely extensively on the support of the microenvironment (including IL-6). Once cells become independent from their microenvironment surroundings, they render more aggressive and do not any longer rely on JunB so extensively.

“We, therefore, hypothesize that inhibition of JunB in early disease may prevent MM progression,” emphasizes Dr Podar.

Results in tumour-cell models that allow the induction of JunB knockdown or JunB activation, respectively, corroborated the functional role of JunB in the production and secretion of these angiogenic factors (AFs).

No unknown player

For Dr Podar and his team which consists of members from Austria, Belgium, China, Germany, Italy and the US, JunB is by no means an unknown player in MM. Indeed, they have analysed the complex functions of this protein in MM pathogenesis for many years.

The present report, which is a continuation of their previous study published in 2017, reveals for the first time that JunB is not only a mediator of MM cell survival, proliferation, and drug resistance, but also a promoter of angiogenic factor transcription and consequently of MM BM angiogenesis.

“Our past studies have already demonstrated that JunB promotes tumour cell proliferation, survival and drug resistance,” says Dr Podar. “The fact that we have now also identified a key role for JunB in the formation of blood vessels within the bone marrow underscores the potential value of therapeutically targeting this protein.”

To arrive at this conclusion the researchers utilized a wide range of methodologies including ChIP-seq, wound healing and in vitro angiogenesis assays as well as an innovative, dynamic 3D model, confocal microscopy and an in vivo model of the MM bone marrow microenvironment.

The impact of JunB on MM BM angiogenesis was finally confirmed in a dynamic 3D model of the BM microenvironment, a xenograft mouse model as well as in patient-derived BM sections.

Efforts are underway to target AP-1 transcription factors such as JunB as a promising strategy in MM therapy the world over.

Besides inhibiting their expression (i.e., by siRNAs, miRNAs), novel approaches to target TFs in general, and AP-1 TFs in particular, include: (1) the disruption of either their interaction with functionally critical protein binding partners or; (2) their binding to the DNA (oligodeoxynucleotide decoys, pyrrole-imidazole polyamides or small molecules); (3) the modulation of their epigenetic binding through DNA methylation, histone methylation or modification; (4) the induction of proteasomal degradation of TFs by altering their ubiquitylation; as well as by utilizing PROteolysis-TArgeting Chimaeras (PROTACs) or Degronomids; (5) the inhibition of TF expression by modulating their regulators (i.e.,
MAPK- or NFκB-signaling molecules); (6) the use of reversible covalent drugs directed against non-conserved cysteines; and (7) the modulation of TF auto-inhibition, explains Dr Podar. Experimental candidates include T-5224, MLN944, SR11302, vertramine, and curcumine.

Ongoing worldwide industrial efforts aim to develop AP-1 targeting molecular glues and PROTACs.

The findings of the new study are published in the journal Leukemia.