HSH2D inhibits the transcriptional activation of the IL-2 promoter, specifically at the RE/AP element of IL-2, which is regulated by CD28, and HSH2D expression contributes to methotrexate resistance in human T-cell acute lymphoblastic leukemia (Shapiro et al., 2004; Pegram et al., 2015). Here, IL2 is linked to T-cell acute lymphoblastic leukemia.