Truncated RUNX1 Generated by the Fusion of RUNX1 to Antisense GRIK2 via a Cryptic Chromosome Translocation Enhances Sensitivity to Granulocyte Colony-Stimulating Factor.

Fusions of the Runt-related transcription factor 1 (RUNX1) with different partner genes have been associated with various hematological disorders. Interestingly, the C-terminally truncated form of RUNX1 andRUNX1fusion proteins are similarly considered important contributors to leukemogenesis. Here, we describe a 59-year-old male patient who was initially diagnosed with acute myeloid leukemia, inv(16)(p13;q22)/CBFB-MYH11(FAB classification M4Eo). He achieved complete remission and negativeCBFB-MYH11status with daunorubicin/cytarabine combination chemotherapy but relapsed 3 years later. Cytogenetic analysis of relapsed leukemia cells revealedCBFB-MYH11negativity and complex chromosomal abnormalities without inv(16)(p13;q22). RNA-seq identified the glutamate receptor, ionotropic, kinase 2 (GRIK2) gene on 6q16 as a novel fusion partner forRUNX1in this case. Specifically, the fusion ofRUNX1to theGRIK2antisense strand (RUNX1-GRIK2as) generated multiple missplicing transcripts. Because extremely low levels of wild-typeGRIK2were detected in leukemia cells,RUNX1-GRIK2aswas thought to drive the pathogenesis associated with theRUNX1-GRIK2fusion. The truncated RUNX1 generated fromRUNX1-GRIK2asinduced the expression of the granulocyte colony-stimulating factor (G-CSF) receptor on 32D myeloid leukemia cells and enhanced proliferation in response to G-CSF. In summary, theRUNX1-GRIK2asfusion emphasizes the importance of aberrantly truncated RUNX1 in leukemogenesis.