Targeting the IKAROS-SAMHD1 axis in KMT2A rearranged B-ALL

Dr. Rachel Rau – Baylor College of Medicine, Houston, TX

Fewer than half of infants diagnosed with B-lymphoblastic leukemia (B-ALL) will survive their disease. Over 85% of infant B-ALL cases harbor chromosomal rearrangements involving the gene, KMT2A (formerly known as MLL). Rearrangements of KMT2A are also present in ~5% of older children and adolescents with B-ALL, and these patients are also at higher risk for persistent disease after induction therapy and relapse compared to those without KMT2A rearrangements. These data highlight that KMT2A-rearranged (KMT2Ar) B-ALL is a chemotherapy-resistant disease in need of novel therapeutic approaches. My lab recently discovered that genetically engineered deletions of IKZF1, the gene encoding the lymphoid transcription factor, IKAROS, in human B-ALL cells, induced greater sensitivity to cytarabine, a nucleoside analog chemotherapy agent. We determined this heightened sensitivity was due to reduced expression of SAMHD1, an enzyme that metabolizes cytarabine. Mining publicly available ChIPseq data we also found strong IKAROS binding peaks in the regulatory region of SAMHD1, implicating IKAROS as a direct regulator of SAMHD1. Accordingly, RNAseq data from pediatric B-ALL samples revealed a highly significant association between IKZF1 and SAMHD1 expression level. Intriguingly, we found that KMT2Ar B-ALL in both infants and non-infants had significantly higher expression of IKZF1 and SAMHD1 than non-KMT2Ar samples. These novel observations led us to postulate that the IKAROS-SAMHD1 axis may be a relevant chemosensitizing target in B-ALL, particularly B-ALL with KMT2Ar. Here we will examine the mechanisms underlying the association between IKZF1 and SAMHD1 expression and explore the efficacy of targeted inhibition of the IKAROS-SAMHD1 axis in KMT2Ar B-ALL. Our results could unveil novel therapeutic approaches for this poor prognosis disease.