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1923 IRF4-BLOC1S5, the First Genomic Fusion Gene Identified in the TEMPI Syndrome

Program: Oral and Poster Abstracts
Session: 651. Multiple Myeloma and Plasma Cell Dyscrasias: Basic and Translational: Poster I
Hematology Disease Topics & Pathways:
Research, Fundamental Science, Plasma Cell Disorders, Diseases, Lymphoid Malignancies
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Jia Liu*, Zilu Zhang*, Wenbin Xu*, Qing Yu*, Ming-Yuan Jia* and Yan Hua, PhD*

Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

The TEMPI syndrome is a rare multi-systemic disease, characterize by telangiectasias, elevated erythropoietin and erythrocytosis, monoclonal gammopathy, perinephric fluid collections, and intrapulmonary shunting (Sykes et al, N Engl J Med 2011). Plasma cell is supposed to play a pathogenic role in the syndrome (Sykes et al, Blood 2020), but the underlying molecular mechanism remains poorly understood. Here, we introduced a novel IRF4-BLOC1S5 fusion gene in the TEMPI syndrome, highly expressed in the monoclonal plasma cell population.

We presented one case of the TEMPI syndrome with typical clinical symptoms. The patient received bortezomib and dexamethasone treatment. After 4 cycles of treatment, the patient achieved a satisfied response with a negative MRD. The symptoms were relieved, with the disappearance of the cyanosis, telangiectasias, perinephric-fluid collection, and serum M protein, amelioration of intrapulmonary shunting, normalization of erythrocyte count and erythropoietin level.

To explore the possible mechanism of the TEMPI syndrome, we performed whole genome sequencing and transcriptome analysis to identify genomic and transcriptomic abnormalities of our patient. WGS of paired tumor (CD138+ plasma cells) and normal samples revealed a somatic inversion on chromosome 6. Bulk RNA-Seq showed that this inversion caused an out-of-frame fusion transcript IRF4-BLOC1S5, which generated a short N-terminal-truncated IRF4 protein. Western blotting confirmed that the corresponding truncated-IRF4 protein was expressed in the CD138+ plasma cells, but not CD138- cells of this patient and normal donors, as well as MM samples.

We performed single cell RNA-sequencing to identify distinct clusters of this patient and found a strong expansion (11.2-fold) of plasma population companied with high expression of truncated-IRF4 in our patient in the case and this unique expanded plasma cluster expressed one specific immunoglobulin clonotype sharing the same CDR3 sequence. Functional analysis illustrated that differentially expressed genes in plasma cells between this patient and healthy controls were enriched in the KEGG pathways such as ribosome and protein processing in endoplasmic reticulum. Besides, the expression of IRF4-BLOC1S5 was only detected at diagnosis and significantly decreased after the BD treatment and in the clinical follow-up (up to 18 months). IRF4-BLOC1S5 may serve as a molecular marker to surveille the disease progression of this patient.

In conclusion, IRF4-BLOC1S5 is the first fusion gene reported in the TEMPI syndrome. IRF4-BLOC1S5 was highly proposed to play an important role in the pathophysiology of the TEMPI syndrome based on the high correlation between IRF4-BLOC1S5 expression level and symptoms of the syndrome. More molecular events responsible for the TEMPI syndrome still await to be identified, albeit a ultrarare occurrence of this disease. An intensive international collaboration is strongly proposed to completely elucidate its molecular mechanisms.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH