The role of splice isoforms of the immune receptor SLAMF6 in the malignant phenotype of hematopoietic cancers

SLAMF6 is a receptor abundantly expressed on hematopoietic-cells. Recently we evaluated two isoforms of the SLAMF6 gene: The `canonical’ receptor and its shorter isoform (SLAMF6^Δ17-65). In a previous work, we showed that SLAMF6^Δ17-65 has a strong agonistic effect, particularly in preventing T-cell apoptosis, while its canonical isoform works as a classical inhibitory checkpoint. In normal lymphocytes, SLAMF6^Δ17-65 comprises only a small proportion of the total SLAMF6 transcript.

We previously evaluated the spliced isoform’s effect for its efficacy in cancer-immunotherapy. In this work, a different angle is taken, assessing if the proactive role of SLAMF6^Δ17-65 in hematopoietic-cells supports unrestrained proliferation and resistance to apoptosis, essential for the malignant transformation.

We hypothesized that hematopoietic-malignancies will be associated with a shift in SLAMF6 transcript, to favor the agonistic isoform. To prove this, we did a genome-wide database exploratory study, with the challenge being that only deep-RNA-sequencing data using a paired-end approach is useful.

SLAMF6 isoform transcripts were compared in T-cell-Lymphoma, AML, DLBCL, CLL and MM samples from NCBI’s SRA datasets generated with Illumina NextSeq-500 or advanced generation. Altogether, 451 samples of hematologic malignancies were analyzed. Patients were divided into High and Low expressors of SLAMF6^Δ17-65. Gene expression signatures were identified, a comparison was made to databases of normal progeny cells and a correlation was made with patients’ survival-time. A set of genes will be presented that correlate with high expression of SLAMF6^Δ17-65.

Thus, altered immune receptor splicing pattern is a new component of pathological cellular circuits that drive or sustain malignancy in hematopoietic-cells.