Inhibition of High Mobility Group Box-1 (HMGB1) Eradicates Human Myelodysplastic Syndrome

Myelodysplastic syndrome (MDS) is a heterogeneous and pre-leukemic clonal stem cell disorder characterized by aberrant hematopoiesis and bone marrow failure. Since MDS is associated with a dysregulated innate immune system, we performed a genetic screen of the human toll-like receptor (TLR) pathway and found that high mobility group box-1 (HMGB1) was abundantly expressed in MDS. HMGB1 is a ubiquitously expressed, non-histone chromatin-binding protein. In solid cancers, high expression of HMGB1 was associated with both shortened progression-free and overall survival, but its role in hematologic malignancies is not well defined. We hypothesized that targeting HMGB1 could be therapeutic in MDS. To study HMGB1 in human MDS, we utilized a cell line, MDS-L, derived from a patient with myelodysplastic syndrome with ring sideroblasts. Morphologically, the cells display dysplastic features, including cytoplasmic vacuolation and prominent, irregular nucleoli. We found that HMGB1 was detected at high levels in both MDS-L and in primary CD34+ MDS compared to CD34+ cord blood and healthy human marrow (*p